CN101870769B - PEG (Polyethylene Glycol), mPEG (Methoxy Polyethylene Glycol) chemical modifier and method thereof for preparing water-soluble resveratrol prodrug - Google Patents
PEG (Polyethylene Glycol), mPEG (Methoxy Polyethylene Glycol) chemical modifier and method thereof for preparing water-soluble resveratrol prodrug Download PDFInfo
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Abstract
The invention discloses a PEG (Polyethylene Glycol)/mPEG (Methoxy Polyethylene Glycol) chemical modifier and a method thereof for preparing a water-soluble resveratrol prodrug. In the PEG/mPEG chemical modifier, PEG or mPEG is used as a vector, and the chemical modifier is prepared through reacting succinic anhydride, bromoacetate or isobutyl bromoacetate with amino acid. The preparation conditions and steps of the chemical modifier are simple. The chemical modifier is used for modifying the resveratrol to prepare the resveratrol prodrug, can change the water solubility and the stability of the resveratrol, is convenient to use and improves the bioactivity. When the prodrug is decomposed in vivo, amino acid required by the human body is also released while the resveratrol is released, thus the application scope of the prodrug is wider than that of the resveratrol.
Description
Technical Field
The invention belongs to the field of compounds and pharmacy, and particularly relates to a PEG (polyethylene glycol) and mPEG (methoxy polyethylene glycol) chemical modifier, a preparation method thereof, and a method for preparing a water-soluble resveratrol prodrug by modifying resveratrol by using the PEG and mPEG chemical modifier as a modifier.
Background
Resveratrol (RES) is a 3, 4', 5-trihydroxystilbene with a chemical name, is a common stilbene compound, widely exists in a plurality of plants such as grapes, giant knotweed rhizome, veratrum and the like, and has pharmacological activities in various aspects such as tumor resistance, bacteria resistance, inflammation resistance, allergy resistance, blood fat reduction, oxidation resistance and the like. However, the resveratrol contains a stilbene mother nucleus structure, so that the resveratrol is poor in water solubility, is difficult to dissolve in water and inconvenient to use, and limits the application range of the resveratrol. In addition, the resveratrol is unstable in property and easy to oxidize, and is easy to convert into a cis-configuration under the irradiation of ultraviolet light, so that the reduction of the biological activity of the resveratrol is caused, and therefore, the key for improving the water solubility and the stability of the resveratrol is to improve the bioavailability and the health-care effect of the resveratrol.
The application of biocompatible high molecular polymer in natural drugs has attracted much attention in recent years, and polyethylene glycol and its derivatives have been widely used as carriers for pharmaceutical preparations in many commercial drugs. Polyethylene glycol (PEG for short) has high hydrophilicity, large hydrodynamic volume in aqueous solution and no immunogenicity, and when it is attached to a drug molecule or the surface of a drug, it can impart its excellent properties to the drug molecule, change their biodistribution behavior and solubility in aqueous solution, and increase the water solubility of the drug. In order to avoid cross-linking and agglomeration in the modification process, monomethoxypolyethylene glycol (mPEG) can also be used as a synthetic raw material of the modifier.
Chinese patent application 2009100710372 discloses a hydrophilic polymer-resveratrol conjugate and a preparation method thereof, which is to prepare the hydrophilic resveratrol conjugate by sequentially carrying out carboxylation reaction and acyl chlorination reaction on monomethoxy polyethylene glycol (mPEG) and monomethoxy polypropylene glycol, and then reacting with resveratrol, wherein compared with the original resveratrol, the product has improved water solubility and stability.
Disclosure of Invention
The invention aims to provide a PEG and mPEG chemical modifier connected with amino acid and a preparation method thereof, wherein the modifier has a simple preparation method, can be used for modifying compound molecules (including drug molecules) so as to change the water solubility and the stability of a modified object, release the amino acid required by a human body while decomposing, increase the functions of the modified compound and have wider application range.
The invention also aims to provide an application of the PEG and mPEG chemical modifier, namely the PEG and mPEG chemical modifier is used for modifying resveratrol to prepare a resveratrol prodrug. The preparation method is simple, the prepared prodrug has good water solubility compared with resveratrol, the stability is improved, the biological activity is improved, the use is convenient, the amino acid necessary for a human body is released while the resveratrol is released by the prodrug, the function of the prodrug is increased, and the application range of the prodrug is wider.
The invention aims to realize the aim, and adopts the technical scheme that:
(1) a PEG and mPEG chemical modifier has the following molecular structural formula:
wherein,
(2) the invention also provides a PEG chemical modifier, the molecular structural formula of which is as follows:
wherein PEG means PEG 5000.
The preparation method of the PEG/mPEG chemical modifier in the item (1) is characterized in that water-soluble PEG or mPEG is used as a carrier, and reacts with succinic anhydride, ethyl bromoacetate or isobutyl bromoacetate to obtain PEG or mPEG carboxylic acid derivatives, and the PEG or mPEG carboxylic acid derivatives are connected with amino acid to prepare the PEG/mPEG chemical modifier.
The preparation methods of the PEG or mPEG carboxylic acid derivatives are divided into two types, wherein: the preparation method carried out by reacting water-soluble carrier with succinic anhydride is carried out according to the following steps:
firstly, reacting a dried carrier and succinic anhydride by using chloroform as a solvent, adding pyridine, and heating and refluxing;
② evaporating the solvent, adding saturated NaHCO3Extracting the solution with ethyl acetate, and adjusting the pH value to 2-3 with dilute hydrochloric acid;
extracting with dichloromethane, drying, concentrating under reduced pressure, adding anhydrous ether, filtering, and vacuum drying to obtain PEG or mPEG carboxylic acid derivative with carboxyl terminal group.
The second preparation method of PEG or mPEG carboxylic acid derivatives is carried out by reacting water-soluble carrier with ethyl bromoacetate or isobutyl bromoacetate, and the preparation method comprises the following steps:
the carrier (PEG or mPEG) is dissolved in toluene, and part of toluene is distilled off. (the purpose of this step is to remove water from the system and to distill off about one fifth of the total amount of toluene)
② placing the mixture to room temperature, adding NaH under ice bath and stirring for 10-20 min;
③ adding ethyl bromoacetate or isobutyl bromoacetate, and carrying out reflux reaction for 20-28 h;
fourthly, after the reaction is finished, filtering, evaporating the filtrate under reduced pressure to remove toluene, dissolving the residue with dichloromethane, concentrating, slowly pouring ether while stirring, separating out white solid, filtering, and drying in vacuum to obtain PEG or mPEG carboxylic ester;
hydrolyzing the carboxylic ester in NaOH solution, and reacting at room temperature for 3-5h under stirring;
sixthly, under the cooling of ice water, regulating the pH value to 2-3 by hydrochloric acid solution, extracting by dichloromethane, combining organic layers, washing by water, drying over night by anhydrous sodium sulfate, removing the dichloromethane by reduced pressure evaporation, and recrystallizing residues by isopropanol to obtain the PEG or mPEG carboxylic acid derivative.
In the preparation method of the PEG or mPEG chemical modifier, the amino acid is one of glycine, alanine, valine, leucine, isoleucine, phenylalanine or tryptophan.
In the preparation method of the PEG and mPEG chemical modifier, the connection between PEG or mPEG carboxylic acid derivatives and amino acids is carried out according to the following steps:
preparing corresponding PEG active ester or mPEG active ester
Dissolving PEG or mPEG carboxylic acid derivatives in dichloromethane, cooling to 0-5 ℃ after dissolving, adding dicyclohexylcarbodiimide and N-hydroxysuccinimide, heating to room temperature, filtering dicyclohexylurea generated in the reaction after the reaction is finished, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying in vacuum to obtain PEG or mPEG active ester;
② preparing target products PEG, mPEG chemical modifier
Dissolving PEG or mPEG active ester in DMF, stirring to dissolve the PEG or mPEG active ester, cooling to 0-5 ℃, and dropwise adding NaHCO of amino acid3And (3) heating the solution to room temperature, stirring for reaction, filtering after the reaction is finished, removing the solvent from the filtrate under reduced pressure, dissolving the residue in a hydrochloric acid solution, extracting with dichloromethane, combining organic layers, washing with water, drying over anhydrous sodium sulfate overnight, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the PEG and mPEG chemical modifiers connected with amino acids, namely the target products PEG and mPEG chemical modifiers.
The invention also provides an application of the PEG and mPEG chemical modifier, which is used for preparing a water-soluble resveratrol prodrug by being connected with resveratrol through an ester bond; the combination mode of the PEG, mPEG chemical modifier and resveratrol is as follows:
the preparation method of the water-soluble resveratrol prodrug is carried out according to the following steps:
dissolving PEG and mPEG chemical modifiers in dichloromethane, and stirring to dissolve the PEG and mPEG chemical modifiers;
reducing the temperature to 0-5 ℃, adding resveratrol, dicyclohexylcarbodiimide and dimethylaminopyridine, heating to room temperature, and stirring for reaction;
③ after the reaction, adding HAc THF solution to decompose excessive dicyclohexylcarbodiimide;
and fourthly, washing with dilute hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing with isopropanol to obtain the resveratrol prodrug.
As optimization of the invention, the molecular weight of PEG and mPEG related in the method for preparing the resveratrol prodrug is 2000-20000. The molecular weights of PEG and mPEG are defined to indicate that both low molecular weight polymeric and high molecular weight polymeric PEG and mPEG chemical modifiers are suitable for use in preparing resveratrol prodrugs.
Compared with the prior art, the invention has the technical progress that:
the PEG or mPEG chemical modifier connected with the amino acid provided by the invention has good chemical properties, the preparation method is simple, the water solubility and the stability of the product are high, and the PEG or mPEG chemical modifier can be used for modifying compound molecules (including drug molecules) such as resveratrol and compounds with alcoholic hydroxyl or phenolic hydroxyl, so that the water solubility and the stability of the compound molecules are improved, the substances are convenient to use, the biological activity is improved, in-vitro release tests prove that the amino acid is released while decomposition is carried out, the characteristic increases the use performance of the substances, and the application range of the substances is wider.
Experiments prove that the water solubility of the resveratrol is improved, the stability is enhanced, the biological activity is improved, the prodrug is convenient to use when used as a medicine, the prodrug is proved to release amino acid required by a human body while being decomposed when in vitro release tests are carried out, the characteristic improves the using performance of the prodrug, and the application range of the prodrug is wider than that of the resveratrol.
The present invention will be described in further detail with reference to specific examples.
Detailed Description
The following examples are intended to illustrate the invention and are not intended to limit the invention.
Example 1 preparation of PEG chemical modifier with PEG6000, further use of the modifier for modifying resveratrol to prepare Water-soluble resveratrol prodrugs
The embodiment comprises the following steps:
(1) preparation of PEG6000 carboxylic acid derivatives
The reaction formula is as follows:
the specific operation process comprises the following steps: dissolving 30g (0.005mol) of dried PEG (polyethylene glycol) in 200mL of chloroform solution, adding 1.5g (0015mol) of succinic anhydride, stirring, adding 2mL of pyridineHeating and refluxing; after 48 hours of reaction, the solvent was evaporated off and the residue was taken up in 100mL of saturated NaHCO3Dissolving the solution, extracting for 3 times by using 30mL of ethyl acetate, and adjusting the pH value of the obtained water phase to 2-3 by using dilute hydrochloric acid; extracting with dichloromethane, mixing organic phases, washing with water to neutrality, drying, concentrating under reduced pressure, adding anhydrous ether, and precipitating white solid PEG6000 carboxylic acid derivative;
(2) synthesis of PEG6000 active ester
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 5g (0.0008mol) of PEG6000 carboxylic acid derivative in 50mL of dichloromethane, cooling to 0-5 ℃, adding 0.33g (0.0016mol) of DCC and 0.18g (0.0016mol) of N-hydroxysuccinimide (NHS) dissolved in 10mL of DMFM, heating to room temperature, after the reaction is finished, filtering to remove dicyclohexylurea generated in the reaction, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the PEG6000 active ester.
(3) Synthesis of PEG6000 chemical modifier connected with glycine
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 3g (0.0005mol) of PEG6000 active ester in 15ml of DMF, stirring to dissolve, cooling to 0-5 ℃, and dropwise adding 0.14g (0.0018mol) of glycine NaHCO3Heating the solution 5ml to room temperature, stirring, reacting, filtering, removing solvent from the filtrate under reduced pressure, dissolving the residue with 5% hydrochloric acid, extracting with dichloromethane, mixing the organic layers, washing with water, drying over anhydrous sodium sulfate overnight, concentrating under reduced pressure, adding anhydrous ether, filtering, and vacuum drying to obtain the final productPEG6000 chemical modifier connected with glycine.
(4) Preparation of resveratrol prodrug by PEG6000 chemical modifier connected with glycine
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 0.5g (0.078mmol) of PEG6000 chemical modifier connected with glycine in dichloromethane, stirring to dissolve, cooling to 0-5 ℃, adding 0.005g (0.24mmol) of resveratrol, 0.06g (0.27mmol) of DDC and 0.03g (0.27mmol) of DMAP, heating to room temperature, stirring to react, after the reaction is finished, adding 10% of HAc THF solution to decompose excessive DCC, washing with 2% diluted hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, recrystallizing with isopropanol to obtain the resveratrol prodrug.
Experiments prove that: the PEG6000 chemical modifier connected with the glycine has good water solubility and stability; the resveratrol prodrug has good water solubility, is convenient to use, improves the biological activity, and releases the resveratrol and the glycine at the same time.
Example 2 preparation of PEG chemical modifier with PEG5000, which is further used to modify resveratrol to prepare Water-soluble resveratrol prodrugs
(1) Preparation of PEG5000 carboxylic acid derivatives
The reaction formula is as follows:
the method comprises the following specific operations: dissolving PEG 500030 g (0.006mol) in 150mL of toluene, evaporating 30mL of toluene, cooling to room temperature, adding 0.43g (0.018mol) of NaH solution in an ice bath, stirring for 15min, dropwise adding 11g (0.066mol) of ethyl bromoacetate, refluxing for 24h, filtering, evaporating toluene from the filtrate under reduced pressure, dissolving the residue with dichloromethane, slowly pouring diethyl ether while stirring to precipitate a white solid, performing suction filtration and vacuum drying to obtain PEG or mPEG carboxylate, hydrolyzing in 120mL of 1mol/L NaOH solution, and reacting at room temperature for 4h while stirring. Under ice water cooling, adjusting pH to 3 with 2mol/L hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying overnight over anhydrous sodium sulfate, removing dichloromethane by evaporation under reduced pressure, and recrystallizing the residue with isopropanol to obtain PEG5000 carboxylic acid derivative.
(2) Synthesis of PEG5000 active ester
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 5g of PEG5000 carboxylic acid derivative (0.001mol) by using 50mL of dichloromethane, cooling to 0-5 ℃, adding 0.41g (0.002mol) of DCC and 0.23g (0.02mol) of N-hydroxysuccinimide (NHS) dissolved in 10mL of DMFM, heating to room temperature, after the reaction is finished, filtering dicyclohexylurea generated in the reaction, decompressing and concentrating, adding anhydrous ether, filtering, and drying in vacuum to obtain the PEG5000 active ester.
(3) Synthesis of proline-linked PEG5000 chemical modifiers
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 3g (0.0006mol) of PEG5000 active ester in 15ml of DMMF, stirring to dissolve the PEG5000 active ester, cooling the temperature to 0-5 ℃, and dropwise adding 0.24g (0.0021mol) of proline NaHCO35ml of solution is added toStirring and reacting at room temperature, filtering after the reaction is finished, removing the solvent from the filtrate under reduced pressure, dissolving the residue with 5% hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying over night with anhydrous sodium sulfate, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the PEG5000 chemical modifier connected with proline.
(4) Modifying resveratrol with PEG5000 chemical modifier connected with proline to prepare resveratrol prodrug
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 0.5g (0.098mmol) of PEG5000 chemical modifier connected with proline in dichloromethane, stirring to dissolve, cooling to 0-5 ℃, adding 0.06g (0.29mmol) of resveratrol, 0.07g (0.34mmol) of DDC and 0.04g (0.34mmol) of DMAP, heating to room temperature, stirring to react, adding 10% of HAc THF solution to decompose excessive DCC after the reaction is finished, washing with 2% diluted hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing with isopropanol to obtain resveratrol prodrug.
Experiments prove that: the PEG5000 chemical modifier connected with proline has good water solubility and stability; the resveratrol prodrug has good water solubility, is convenient to use, improves the biological activity, and releases proline while releasing resveratrol.
Example 3 preparation of PEG chemical modifier with mPEG4000, which is further used to modify resveratrol to prepare Water-soluble resveratrol prodrugs
(1) Preparation of mPEG4000 carboxylic acid derivatives
The reaction formula is as follows:
the method comprises the following specific operations: dissolving mPEG 400030 g (0.0075mol) in 150mL of toluene, evaporating 30mL of toluene, cooling to room temperature, adding 0.27g (0.011mol) of solution in an ice bath, stirring for 20min, dropwise adding 8.5g (0.045mol) of isopropyl bromoacetate, refluxing for 20h, filtering, evaporating toluene from the filtrate under reduced pressure, dissolving the residue with dichloromethane, slowly pouring diethyl ether while stirring, precipitating a white solid, performing suction filtration, drying in vacuum to obtain PEG or mPEG carboxylic ester, hydrolyzing in 120mL of NaOH solution with the concentration of 1mol/L, and reacting at room temperature for 3h while stirring. Cooling with ice water, adjusting pH to 3 with 2mol/L hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying overnight with anhydrous sodium sulfate, evaporating dichloromethane under reduced pressure, and recrystallizing the residue with isopropanol to obtain mPEG4000 carboxylic acid derivative;
(2) synthesis of mPEG4000 active ester
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 5g (0.0012mol) of mPEG4000 carboxylic acid derivative with 50mL of dichloromethane, cooling to 0-5 ℃, adding 0.25g (0.0012mol) of DCC and 0.14g (0.0012mol) of N-hydroxysuccinimide (NHS) dissolved in 10mLDFM, heating to room temperature, after the reaction is finished, filtering dicyclohexylurea generated in the reaction, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying in vacuum to obtain the mPEG4000 active ester.
(3) Synthesis of alanine-linked mPEG4000 chemical modifier
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 3g (0.0007mol) of mPEG4000 active ester in 15ml of DMMF, stirring to dissolve the mPEG4000 active ester, cooling the temperature to 0-5 ℃, and dropwise adding 0.12g (0.0014mol) of NaHCO of alanine3And (3) raising the solution to room temperature, stirring for reaction, completing reaction, filtering, removing the solvent from the filtrate under reduced pressure, dissolving the residue with 5% hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying over anhydrous sodium sulfate overnight, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the mPEG4000 chemical modifier connected with alanine.
(4) Modification of resveratrol by mPEG4000 chemical modifier connected with alanine to prepare resveratrol prodrug
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 0.5g (0.12mmol) of mPEG4000 chemical modifier connected with alanine in dichloromethane, stirring to dissolve, cooling to 0-5 ℃, adding 0.005g (0.24mmol) of resveratrol, 0.05g (0.24mmol) of DDC and 0.03g (0.24mmol) of DMAP, heating to room temperature, stirring to react, after the reaction is finished, adding 10% of HAc THF solution to decompose excessive DCC, washing with 2% diluted hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing with isopropanol to obtain the resveratrol prodrug.
Experiments prove that: the mPEG4000 chemical modifier connected with alanine has good water solubility and stability; the resveratrol prodrug has good water solubility, is convenient to use, improves the biological activity, and releases the alanine while releasing the resveratrol.
Example 4 preparation of PEG chemical modifier with mPEG4000, which is further used to modify resveratrol to prepare Water-soluble resveratrol prodrugs
(3) Preparation of mPEG4000 carboxylic acid derivatives
The reaction formula is as follows:
the method comprises the following specific operations: dissolving mPEG 400030 g (0.0075mol) in 150mL of toluene, evaporating 30mL of toluene, cooling to room temperature, adding 0.27g (0.011mol) of solution in an ice bath, stirring for 10min, dropwise adding 8.5g (0.045mol) of isopropyl bromoacetate, refluxing for 28h, filtering, evaporating toluene from the filtrate under reduced pressure, dissolving the residue with dichloromethane, slowly pouring diethyl ether while stirring, precipitating a white solid, performing suction filtration, and vacuum drying to obtain PEG or mPEG carboxylic ester, hydrolyzing in 120mL of NaOH solution with the concentration of 1mol/L, and reacting at room temperature for 5h while stirring. Cooling with ice water, adjusting pH to 3 with 2mol/L hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying overnight with anhydrous sodium sulfate, evaporating dichloromethane under reduced pressure, and recrystallizing the residue with isopropanol to obtain mPEG4000 carboxylic acid derivative;
(4) synthesis of mPEG4000 active ester
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 5g (0.0012mol) of mPEG4000 carboxylic acid derivative in 50mL of dichloromethane, cooling to 0-5 ℃, adding 0.25g (0.0012mol) of DCC and 0.14g (0.0012mol) of N-hydroxysuccinimide (NHS) dissolved in 10mL of DMFM, heating to room temperature, after the reaction is finished, filtering dicyclohexylurea generated in the reaction, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying in vacuum to obtain the mPEG4000 active ester.
(3) Synthesis of alanine-linked mPEG4000 chemical modifier
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 3g (0.0007mol) of mPEG4000 active ester in 15ml DMF, stirring to dissolve the mPEG4000 active ester, cooling the temperature to 0-5 ℃, and dropwise adding 0.12g (0.0014mol) of NaHCO of alanine3And (3) raising the solution to room temperature, stirring for reaction, completing reaction, filtering, removing the solvent from the filtrate under reduced pressure, dissolving the residue with 5% hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying over anhydrous sodium sulfate overnight, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the mPEG4000 chemical modifier connected with alanine.
(4) Modification of resveratrol by mPEG4000 chemical modifier connected with alanine to prepare resveratrol prodrug
The reaction formula is as follows:
the method comprises the following specific operations: dissolving 0.5g (0.12mmol) of mPEG4000 chemical modifier connected with alanine in dichloromethane, stirring to dissolve, cooling to 0-5 ℃, adding 0.005g (0.24mmol) of resveratrol, 0.05g (0.24mmol) of DDC and 0.03g (0.24mmol) of DMAP, heating to room temperature, stirring to react, after the reaction is finished, adding 10% of HAc THF solution to decompose excessive DCC, washing with 2% diluted hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing with isopropanol to obtain the resveratrol prodrug.
Experiments prove that: the mPEG4000 chemical modifier connected with alanine has good water solubility and stability; the resveratrol prodrug has good water solubility, is convenient to use, improves the biological activity, and releases the alanine while releasing the resveratrol.
Of course, the embodiments of the present invention are not limited to the above embodiments, and various features and various equivalent changes between the features may be implemented in various forms, for example, the types of amino acids may be selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan and proline; the molecular weight of PEG and mPEG can be adjusted between 2000 and 20000; the specific numerical values of the control conditions in the production method may be adjusted within the ranges defined in the claims, and the like. PEG chemical modifiers, methods of making them, uses of them, and methods of making water-soluble resveratrol prodrugs with them as modifiers, all without departing from the spirit of the claims, are considered to be within the scope of the invention.
Claims (10)
1. A PEG and mPEG chemical modifier is characterized in that the molecular structural formula is as follows:
wherein,
2. a PEG chemical modifier is characterized in that the molecular structural formula is as follows:
3. A method for preparing PEG, mPEG chemical modifiers according to claim 1, characterized in that: the PEG and mPEG chemical modifier is prepared by taking water-soluble PEG or mPEG as a carrier, reacting with succinic anhydride, ethyl bromoacetate or isobutyl bromoacetate to obtain a PEG or mPEG carboxylic acid derivative, and connecting the PEG or mPEG carboxylic acid derivative with amino acid.
4. The preparation method of the PEG and mPEG chemical modifier according to claim 3, is characterized in that: the PEG or mPEG carboxylic acid derivative is prepared by reacting a water-soluble carrier PEG, mPEG and succinic anhydride, and the preparation method comprises the following steps:
firstly, reacting a dried carrier and succinic anhydride by using chloroform as a solvent, adding pyridine, and heating and refluxing;
② evaporating the solvent, adding saturated NaHCO3Extracting the solution with ethyl acetate, and adjusting the pH value to 2-3 with dilute hydrochloric acid;
extracting with dichloromethane, drying, concentrating under reduced pressure, adding anhydrous ether, filtering, and vacuum drying to obtain PEG or mPEG carboxylic acid derivative.
5. The method for preparing PEG/mPEG chemical modifiers according to claim 3, characterized in that: the PEG or mPEG carboxylic acid derivative is prepared by reacting a water-soluble carrier PEG, mPEG and ethyl bromoacetate or isobutyl bromoacetate, and the preparation method comprises the following steps:
dissolving a carrier in toluene, and evaporating partial toluene;
② placing the mixture to room temperature, adding NaH under ice bath and stirring for 10-20 min;
③ adding ethyl bromoacetate or isobutyl bromoacetate, and carrying out reflux reaction for 20-28 h;
fourthly, after the reaction is finished, filtering, evaporating the filtrate under reduced pressure to remove toluene, dissolving the residue with dichloromethane, concentrating, slowly pouring ether while stirring, separating out white solid, filtering, and drying in vacuum to obtain PEG or mPEG carboxylic ester;
hydrolyzing the carboxylic ester in NaOH solution, and reacting at room temperature for 3-5h under stirring;
sixthly, under the cooling of ice water, regulating the pH value to 2-3 by hydrochloric acid solution, extracting by dichloromethane, combining organic layers, washing by water, drying over night by anhydrous sodium sulfate, removing the dichloromethane by reduced pressure evaporation, and recrystallizing residues by isopropanol to obtain the PEG or mPEG carboxylic acid derivative.
6. The method of preparing PEG, mPEG chemical modifiers according to any of the claims from 3 to 5, characterized in that: the amino acid is one of glycine, alanine, valine, leucine, isoleucine, phenylalanine or tryptophan.
7. The method for preparing PEG, mPEG chemical modifiers according to any of the claims from 3 to 5, characterized in that: the preparation method for preparing the PEG/mPEG chemical modifier by connecting PEG or mPEG carboxylic acid derivatives with amino acids is carried out according to the following steps:
preparing corresponding PEG active ester or mPEG active ester
Dissolving PEG or mPEG carboxylic acid derivatives in dichloromethane, cooling to 0-5 ℃ after dissolving, adding dicyclohexylcarbodiimide and N-hydroxysuccinimide, heating to room temperature, filtering dicyclohexylurea generated in the reaction after the reaction is finished, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying in vacuum to obtain PEG or mPEG active ester;
② preparing target products PEG, mPEG chemical modifier
Dissolving PEG or mPEG active ester in DMF, stirring to dissolve the PEG or mPEG active ester, cooling to 0-5 ℃, and dropwise adding NaHCO of amino acid3And (3) heating the solution to room temperature, stirring for reaction, filtering after the reaction is finished, removing the solvent from the filtrate under reduced pressure, dissolving the residue in a hydrochloric acid solution, extracting with dichloromethane, combining organic layers, washing with water, drying over night with anhydrous sodium sulfate, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the PEG chemical modifier connected with amino acid, namely the target products PEG and mPEG chemical modifiers.
8. The method for preparing PEG/mPEG chemical modifiers according to claim 6, characterized in that: the preparation method for preparing the PEG/mPEG chemical modifier by connecting PEG or mPEG carboxylic acid derivatives with amino acids is carried out according to the following steps:
preparing corresponding PEG active ester or mPEG active ester
Dissolving PEG or mPEG carboxylic acid derivatives in dichloromethane, cooling to 0-5 ℃ after dissolving, adding dicyclohexylcarbodiimide and N-hydroxysuccinimide, heating to room temperature, filtering dicyclohexylurea generated in the reaction after the reaction is finished, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying in vacuum to obtain PEG or mPEG active ester;
② preparing target products PEG, mPEG chemical modifier
Dissolving PEG or mPEG active ester in DMF, stirring to dissolve the PEG or mPEG active ester, cooling to 0-5 ℃, and dropwise adding NaHCO of amino acid3And (3) heating the solution to room temperature, stirring for reaction, filtering after the reaction is finished, removing the solvent from the filtrate under reduced pressure, dissolving the residue in a hydrochloric acid solution, extracting with dichloromethane, combining organic layers, washing with water, drying over night with anhydrous sodium sulfate, concentrating under reduced pressure, adding anhydrous ether, filtering, and drying under vacuum to obtain the PEG chemical modifier connected with amino acid, namely the target products PEG and mPEG chemical modifiers.
9. A preparation method of a water-soluble resveratrol prodrug is characterized in that: linking a PEG, mPEG chemical modifier as defined in claim 1 to resveratrol via an ester linkage to produce a water-soluble resveratrol prodrug; wherein the PEG and mPEG are chemical modifiers
The preparation method of the water-soluble resveratrol prodrug is carried out according to the following steps:
dissolving PEG and mPEG chemical modifiers in dichloromethane, and stirring to dissolve the PEG and mPEG chemical modifiers;
reducing the temperature to 0-5 ℃, adding resveratrol, dicyclohexylcarbodiimide and dimethylaminopyridine, heating to room temperature, and stirring for reaction;
③ after the reaction, adding HAc THF solution to decompose excessive dicyclohexylcarbodiimide;
and fourthly, washing with dilute hydrochloric acid, extracting with dichloromethane, combining organic layers, washing with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing with isopropanol to obtain the resveratrol prodrug.
10. The method of preparing a water-soluble resveratrol prodrug according to claim 9, wherein: the molecular weight of the PEG and mPEG is 2000-20000.
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| CN102250342B (en) * | 2011-05-26 | 2013-06-19 | 河北科技大学 | PEG/mPEG (Polyethylene Glycol) multi-carboxyl chemical modifying agent connected with citric acid, preparation method and application thereof in modification of toluylene compound |
| CN102321239B (en) * | 2011-05-30 | 2013-12-11 | 河北科技大学 | Preparation method of water-soluble toluylene compound prodrugs |
| CN102964587A (en) * | 2012-11-09 | 2013-03-13 | 河南工业大学 | Preparation method and application of acid or active ester of polyethylene glycol with tail end connected with proline |
| CN102964588A (en) * | 2012-11-09 | 2013-03-13 | 河南工业大学 | Preparation method and application of acid or active ester of polyethylene glycol with tail end connected with aminophenyl propionic acid |
| JP2017505778A (en) * | 2014-01-29 | 2017-02-23 | ヒューメディックス カンパニー，リミテッド | PEGylated 7-dehydrocholesterol derivatives |
| CN106366305A (en) * | 2016-08-17 | 2017-02-01 | 江苏三宝邦佑生物科技有限公司 | Preparation method for polyethylene glycol methyl ether acetate |
| CN107998403B (en) * | 2017-12-11 | 2021-07-27 | 陈西敬 | PEG-modified water-soluble prodrugs of triacontanol |
| CN113831529A (en) * | 2020-06-24 | 2021-12-24 | 江苏众红生物工程创药研究院有限公司 | Preparation method of monomethoxy polyethylene glycol carboxylic acid and functional derivative thereof |
| CN113181370A (en) * | 2021-05-18 | 2021-07-30 | 六安市康恒生物科技有限公司 | Synthesis process of tumor targeting drug |
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