CN112618729A - Preparation method and application of tripterine-chitosan oligosaccharide coupling drug - Google Patents
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Abstract
The invention relates to a preparation method and application of a tripterine-chitosan oligosaccharide coupling drug, which can effectively solve the problems of high toxic and side effects, poor water solubility and short biological half-life period of tripterine, and the technical scheme for solving the problems is that the structural formula is as follows:wherein the molecular weight of the chitosan oligosaccharide (CSO) is 320-3200Da, and the acetyl contentThe amount z is 0.1-0.8 (percent), x + y + z is 1-20, the reaction condition is mild, the controllability is strong, the yield is high, the water solubility of the final product is good, and the prepared conjugate has good attenuation effect and is an innovation in the preparation method of the tripterine-chitosan oligosaccharide conjugate.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and application of a tripterine-chitosan oligosaccharide coupling drug.
Background
Tripterine (CEL), also known as celastrol, is a quinone methyl triterpenoid extracted from the root of Tripterygium wilfordii, has wide anticancer, anti-inflammatory and weight-reducing effects, is widely applied to the treatment of diseases such as rheumatoid arthritis, systemic lupus erythematosus and chronic nephritis clinically, and can play the anti-inflammatory and anti-tumor effects through various ways. In the research, the tripterine can also obviously reduce the weight of an obese mouse (DIO), and the tripterine is found to be a leptin sensitizer and can reduce the weight by increasing the sensitivity of leptin, so that the tripterine becomes the most effective weight-reducing drug reported so far and is widely used for anti-obesity research. However, the clinical application of tripterine is greatly limited due to the defects of poor water solubility, high toxicity, poor stability and the like of the tripterine. Previous studies have shown that the 20 th carboxylic acid position of tripterine can be easily modified and the physiological effects of the derivative can be unaffected. Therefore, it is very important to improve the solubility and stability and reduce the toxicity by this method.
Chitosan is a low molecular weight product with good water solubility, large functional effect and high bioactivity, has no toxicity, can be applied as a good carrier material, and is widely applied to the fields of medical fibers, medical dressings, drug sustained release materials, gene transduction carriers and biomedicine in recent years.
Currently, chitosan oligosaccharide is used as a basic skeleton, and tripterine is coupled to the skeleton through covalent bonds to obtain a macromolecular prodrug. After the prodrug is absorbed, tripterine is liberated through hydrolysis, so that the research of exerting the drug effect is not reported yet.
Disclosure of Invention
In view of the above situation, the present invention aims to provide a preparation method and application of a tripterine-chitosan oligosaccharide conjugate drug, which can effectively solve the problems of high toxic and side effects, poor water solubility and short biological half-life of tripterine.
The technical scheme of the invention is that the tripterine-chitosan oligosaccharide coupling drug has a structural formula as follows:
wherein the molecular weight of the chitosan oligosaccharide (CSO) is 320-3200Da, the acetyl content z is 0.1-0.8 (percent), and x + y + z is 1-20.
The preparation method of the tripterine-chitosan oligosaccharide coupling drug comprises the following steps:
1) in DMSO (Cel: DMSO ═ 10: 1-50: 1, w/v) adding CEL and a combined catalyst EDC/HOBt, wherein the molar ratio of the CEL to the EDC to the HOBt is 1: 1-3, the reaction temperature is 0-25 ℃, and stirring and reacting for 3-8 h to obtain activated ester;
2) the CSO was dissolved in DMSO at 40-80 ℃ (CSO: DMSO is 50-200: 1, w/v), after dissolving and cooling to 25 ℃, dropwise adding the activated ester obtained in the step 1), reacting at 0-25 ℃, stirring and reacting for 8-24 hours to perform an amide chemical reaction, thereby obtaining the tripterine-chitosan oligosaccharide coupling drug.
The mass concentration ratio of CEL (tripterine) to DMSO (dimethyl sulfoxide) is 10-50: 1.
the mass concentration ratio of CSO (chitosan oligosaccharide) to DMSO (dimethyl sulfoxide) is 50-200: 1.
the tripterine-chitosan oligosaccharide coupling drug is applied to the treatment of obesity, cancer and inflammation.
The invention has mild reaction condition, strong controllability, high yield and good water solubility of final products, the prepared conjugate has good attenuation function, and the weight of the mouse can be remarkably reduced by intragastric administration to an obesity model mouse, thus the invention is an innovation on the preparation method of the tripterine-chitosan oligosaccharide conjugate drug.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of the present invention.
FIG. 2 is a NMR chart of Cel-CSO, which contains characteristic peak regions of Cel and CSO, respectively, indicating that Cel and CSO are synthesized successfully.
FIG. 3 is a graph showing the change of body weight of obese model mice in 21 days after gavage administration of tripterine technical material and tripterine-chitosan oligosaccharide.
FIG. 4 is a graph showing the change in food consumption during 21 days after administration of tripterine and tripterine-chitosan oligosaccharide via gavage in an obese model mouse (P < 0.05vs. model group, P < 0.01vs. model group).
Fig. 5 is a graph of blood lipid levels (. P < 0.05vs. model group,. P < 0.01vs. model group) in groups of mice 21 days after administration.
Fig. 6 is a graph of the liver and epididymal fat coefficients ([ P ] < 0.05vs. model group, [ P ] < 0.01vs. model group) of the groups of mice 21 days after administration.
FIG. 7 is a photograph of HE stained sections of adipose tissues and liver of each group of mice 21 days after the administration.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples.
Example 1
The synthesis steps of the tripterine-chitosan oligosaccharide coupling drug I (CEL-CSO1) are as follows:
1) activating tripterine
Weighing 100mg (0.22mmol) of tripterine, dissolving the tripterine in 3mL of dimethyl sulfoxide, then respectively adding 64mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 0.33mmol) and 45mg of 1-hydroxybenzotriazole (HOBt, 0.33mmol), stirring and activating for 6h at 25 ℃, after the reaction is finished, purifying a wet sample by a silica gel chromatographic column (mobile phase CH2Cl2/CH3OH, 30-20: 1), and then spin-drying the mobile phase to obtain 88.7mg of a solid product (71%);
2) synthesis of coupled drug CEL-CSO1
Weighing 800mg of chitosan oligosaccharide (MW 1000) and dissolving in dimethyl sulfoxide at 55 ℃, cooling to 25 ℃ after dissolving, dropwise adding activated tripterine, stirring for 24 hours at 25 ℃, transferring the reaction solution into a dialysis bag with the molecular weight cutoff of 500Da, dialyzing for 24 hours at low temperature by using double distilled water, changing water every 6 hours, collecting the liquid in the bag, and freeze-drying to obtain 783mg of a target product.
Example 2
The synthesis steps of the tripterine-chitosan oligosaccharide coupling drug II (CEL-CSO3) are as follows:
1) activating tripterine
Weighing 100mg (0.22mmol) of tripterine, dissolving in 3mL of dimethyl sulfoxide, adding 64mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 0.33mmol) and 45mg of 1-hydroxybenzotriazole (HOBt, 0.33mmol) respectively, stirring and activating at 25 ℃ for 6h, after the reaction is finished, purifying by a silica gel chromatographic column by a wet method (mobile phase CH2Cl2/CH3OH,30: 1-20: 1), and then spin-drying the mobile phase to obtain 88.7mg of a solid product (71%).
2) Synthesis of coupled drug CEL-CSO3
Weighing 800mg of chitosan oligosaccharide (MW 3000) to dissolve in dimethyl sulfoxide under the condition of 55 ℃, cooling to 25 ℃ after dissolution, dropwise adding activated tripterine, stirring for 24h at 25 ℃, transferring reaction liquid into a dialysis bag with the molecular weight cutoff of 500Da, dialyzing for 24h at low temperature by double distilled water, changing water every 6h, collecting the liquid in the bag, and freeze-drying to obtain 702mg of a target product.
The following performance tests were performed using tripterine-chitosan oligosaccharide conjugate drug one (CEL-CSO1) as an example:
the synthesis route diagram of tripterine-chitosan oligosaccharide in the first example is shown in fig. 1, the structural representation is nuclear magnetic resonance hydrogen spectrum (1H-NMR), and the conjugate prepared by repeated synthesis has high drug-loading rate and high water solubility, and Cel-CSO has good weight-reducing effect, and the related experimental data are as follows:
first, structural characterization of Cel-CSO conjugate drug in example 1:
(1) taking the coupling drug one as an example, the synthesis route diagram is shown in fig. 1, and the nuclear magnetic resonance hydrogen spectrum characterization is only performed on the final result Cel-CSO:
the peak at 8.0-1.0 is the characteristic peak type of tripterine, the peak at 5.0-3.0 is the peak of chitosan oligosaccharide, and the result shows that the nuclear magnetic resonance hydrogen spectrum of Cel-CSO has the peaks of both tripterine and chitosan oligosaccharide, indicating the successful synthesis (see figure 2).
(2) And (3) testing the drug loading capacity:
dissolving 10mg of Cel-CSO conjugate in 3mL of purified water, diluting 300 mu L of the Cel-CSO conjugate with the purified water to 3mL, measuring the absorbance value of the Cel-CSO conjugate at 425nm by using an ultraviolet spectrophotometer, and obtaining the drug loading according to a standard curve of the tripterine concentration and the absorbance: (9.72. + -. 0.67)%.
(3) Water solubility test:
dissolving 20mg of Cel-CSO conjugate in 1mL of purified water, diluting 500 mu L of the Cel-CSO conjugate with the purified water to 3mL, diluting 500 mu L of the Cel-CSO conjugate with the purified water to 4mL, measuring the absorbance value of the Cel-CSO conjugate at 425nm by using an ultraviolet spectrophotometer, and obtaining the water solubility of the Cel-CSO conjugate according to a standard curve of the tripterine concentration and the absorbance: 18.37. + -. 0.97 mg/mL.
(4) And (3) stability testing:
40mg of the Cel-CSO conjugate was dissolved in 4mL of PBS (pH7.4), gastric juice simulant (pH1.2), intestinal juice simulant (pH7.2), and cell culture medium (10% FBS), incubated at 37 ℃ for 24 hours, and 100. mu.L of each was taken at the same time point, extracted with 1mL of ethyl acetate, and measured by HPLC, and the following results were obtained:
cel concentration% | 30min | 1h | 2h | | 8h | 12h | 24h | |
PBS | 0.9 | 2.9 | 5.2 | 7.2 | 8.5 | 9.4 | 9.7 | |
Serum | 6.0 | 16.2 | 27.0 | 35.0 | 39.5 | 38.0 | 41.4 | |
Culture medium | 8.0 | 19.3 | 42.6 | 61.8 | 69.4 | 70.4 | 70.6 | |
Gastric juice | 1.9 | 6.4 | 10.4 | 19.4 | 23.4 | 21.6 | 23.3 | |
Intestinal juice | 3.8 | 10.7 | 17.1 | 25.9 | 31.4 | 32.8 | 31.0 |
(5) Cytotoxicity experiments:
cel and Cel-CSO were measured for percent cell viability by MTT method, respectively. The L02 cells were plated at 1 × 104 cells/well in a 96-well plate and divided into a blank group (no cells), a control group (cells-containing, no drug-added), and an administration group. After adding the reagent, incubating for 24h at 37 ℃, adding 20 mu L of MTT solution into each hole, continuing incubating for 4h, then discarding the supernatant, adding 150 mu L of DMSO solution into each hole, shaking for 10min, and measuring the OD value at 490nm on an enzyme-linked immunosorbent assay.
Cell viability (%) - (a dose group-a blank)/(a control group-a blank) × 100%
In FIG. 3, the concentrations of Cel and Cel-CSO in the L02 cytotoxicity experiment were:
0.5, 1, 2, 4, 6, 8, 10 μmol/L (effective Cel concentration) incubation for 24h, results show: IC50 for Cel is: 4.65 plus or minus 0.32; IC50 for Cel-CSO is: 7.65. + -. 0.78, Cel-CSO has attenuation effect on Cel.
Second, pharmacodynamic experiment of Cel-CSO conjugate drug in example 1:
selecting 3-week-old C57BL/6J male mice, adaptively feeding for 1 week, and then carrying out obesity molding on the mice with 60% high-fat feed, wherein the mice with the weight more than 20% of that of a normal group are considered as successful molding, and the molding period is 4 months. Mice successfully modeled are divided into a model group, a Cel group (9mg/kg) and a Cel-CSO low-high group (5, 7 and 9mg/kg), 8 mice in each group are respectively subjected to intragastric administration of corresponding medicaments, the administration volume is 100 mu L/10g, the model group and the normal group are subjected to intragastric administration of corresponding doses of physiological saline for 21 days, and the weight and the food consumption of the mice per day are recorded in the period.
(1) The body weight change curves of the mice show: the weight of mice can be reduced by the administration group, wherein the weight reducing effect of the Cel group and the high-dose group of the Cel-CSO is the best, as shown in figure 3.
(2) The diet profile of the mice shows: the administration groups can reduce the food consumption of mice, wherein the food consumption of the Cel group and the high-dose group in the Cel-CSO is obviously reduced (P is less than 0.01), as shown in figure 4.
(3) The blood lipid level profile of the mice shows: the administration group can reduce the content of total cholesterol, triglyceride and low density lipoprotein in the serum of mice and increase the level of high density lipoprotein, and Cel-CSO has better effect of reducing the content of total cholesterol, triglyceride and low density lipoprotein than the Cel group, as shown in figure 5.
(4) The organ coefficient map of the mice shows: the administration group can significantly reduce the fat coefficients of the liver and epididymis, as shown in fig. 6.
(5) HE sections of liver and adipose tissue of mice showed: the mice in the administration group had significantly reduced liver vacuolization and significantly smaller adipose tissue cell volume, as shown in fig. 7.
Through repeated experiments, the other examples can obtain the same or similar experimental results as the example 1, and the detailed description is omitted.
In conclusion, the tripterine-chitosan oligosaccharide (Cel-CSO) has good in-vitro stability and drug loading capacity, greatly improves water solubility, has an obvious attenuation effect, and can remarkably inhibit the food consumption so as to reduce the weight of a mouse.
Compared with the prior art, the technical scheme of the invention has the following advantages:
1. the celastrol-chitosan oligosaccharide coupling drug provided by the invention is characterized in that firstly, celastrol reacts with a combined catalyst EDC/Hobt to obtain an activated ester which can directly react with free amine on chitosan oligosaccharide to obtain a CEL-CSO coupling drug.
2. In the preparation method, chitosan oligosaccharide with the molecular weight of 320-3200Da is preferably used as a substance for providing amino groups in the reaction, and the obtained CEL-CSO has the highest yield of 80-90%.
3. According to the tripterine-chitosan oligosaccharide coupling drug, the chitosan oligosaccharide serving as a carrier raw material has the advantages of good water solubility, biodegradability, cell affinity, no toxicity, no harm, low price and the like, and the coupling drug CEL-CSO has better water solubility and lower toxic and side effects than CEL.
Claims (6)
2. The method for preparing the tripterine-chitosan oligosaccharide conjugate drug of claim 1, which is characterized by comprising the following steps:
1) adding CEL and a combined catalyst EDC/HOBt into DMSO, wherein the molar use ratio of the CEL to the EDC to the HOBt is 1: 1-3, the reaction temperature is 0-25 ℃, and stirring and reacting for 3-8 h to obtain activated ester;
2) dissolving CSO in DMSO at 40-80 ℃, dropwise adding the activated ester obtained in the step 1) after dissolving and cooling to 25 ℃, wherein the reaction temperature is 0-25 ℃, and stirring for reaction for 8-24 hours to generate an amide chemical reaction, so as to obtain the tripterine-chitosan oligosaccharide coupling drug;
the mass concentration ratio of CEL to DMSO is 10-50: 1;
the mass concentration ratio of CSO to DMSO is 50-200: 1.
3. the method for preparing a tripterine-chitosan oligosaccharide conjugate drug according to claim 2, wherein the synthesis of the conjugate drug CEL-CSO1 comprises the following steps:
1) activating tripterine
Weighing 100mg of tripterine, dissolving the tripterine into 3mL of dimethyl sulfoxide, respectively adding 64mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 45mg of 1-hydroxybenzotriazole, stirring and activating at 25 ℃ for 6h, purifying a sample by a silica gel chromatographic column after the reaction is finished, and then carrying out rotary drying on a mobile phase to obtain 88.7mg of a solid product;
2) synthesis of coupled drug CEL-CSO1
Weighing 800mg of chitosan oligosaccharide, dissolving in dimethyl sulfoxide at 55 ℃, cooling to 25 ℃ after dissolving, dropwise adding activated tripterine, stirring for 24 hours at 25 ℃, transferring reaction liquid into a dialysis bag with molecular weight cutoff of 500Da, dialyzing for 24 hours at low temperature by using double distilled water, changing water every 6 hours, collecting liquid in the bag, and freeze-drying to obtain 783mg of target product.
4. The method for preparing a tripterine-chitosan oligosaccharide conjugate drug according to claim 2, wherein the synthesis of the conjugate drug CEL-CSO3 comprises the following steps:
1) activating tripterine
Weighing 100mg of tripterine, dissolving the tripterine into 3mL of dimethyl sulfoxide, respectively adding 64mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 45mg of 1-hydroxybenzotriazole, stirring and activating at 25 ℃ for 6h, purifying a sample by a silica gel chromatographic column by a wet method after the reaction is finished, and then carrying out rotary drying on a mobile phase to obtain 88.7mg of a solid product.
2) Synthesis of coupled drug CEL-CSO3
Weighing 800mg of chitosan oligosaccharide, dissolving in dimethyl sulfoxide at 55 ℃, cooling to 25 ℃ after dissolving, dropwise adding activated tripterine, stirring for 24h at 25 ℃, transferring the reaction solution into a dialysis bag with the molecular weight cutoff of 500Da, dialyzing for 24h at low temperature by using double distilled water, changing water every 6h, collecting the liquid in the bag, and freeze-drying to obtain 702mg of a target product.
5. The use of the tripterine-chitosan oligosaccharide conjugate of claim 1 as a prodrug for the treatment of obesity, cancer, inflammation.
6. The use of the tripterine-chitosan oligosaccharide conjugate drug prepared by the method for preparing the tripterine-chitosan oligosaccharide conjugate drug according to any one of claims 2-4 in the treatment of obesity, cancer and inflammation.
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