CN113181370A - Synthesis process of tumor targeting drug - Google Patents
Synthesis process of tumor targeting drug Download PDFInfo
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- CN113181370A CN113181370A CN202110542460.7A CN202110542460A CN113181370A CN 113181370 A CN113181370 A CN 113181370A CN 202110542460 A CN202110542460 A CN 202110542460A CN 113181370 A CN113181370 A CN 113181370A
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- polyethylene glycol
- resveratrol
- glycine
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- tumor targeting
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Classifications
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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- C08G65/3314—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing a hydroxy group cyclic
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- C08G65/3317—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing a hydroxy group cyclic aromatic phenolic
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
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- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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Abstract
The invention discloses a synthesis process of a tumor targeting drug, which comprises the following steps: purifying and pretreating a reaction raw material N, N-dimethylformamide; synthesizing polyethylene glycol carboxylic acid; synthesizing polyethylene glycol-resveratrol; synthesizing polyethylene glycol-glycine; synthesizing polyethylene glycol-glycine-resveratrol; weighing polyethylene glycol-glycine-resveratrol; the performance parameters of the samples were tested. Compared with the solubility of a resveratrol raw material, the solubility of the prepared polyethylene glycol-glycine-resveratrol is greatly improved, the light stability and the acid-base stability of the polyethylene glycol-glycine-resveratrol are improved, the polyethylene glycol-glycine-resveratrol still has antioxidant activity and anticancer activity, the synthesis process bonds polyphenol-resveratrol and a high polymer to form a targeted drug, the preparation process is simplified, the obtained polyethylene glycol-glycine-resveratrol has good biocompatibility, and the tumor can be effectively treated.
Description
Technical Field
The invention relates to the field of antitumor pharmacology, in particular to a synthesis process of a tumor targeting drug.
Background
The resveratrol is a non-flavonoid polyphenol compound, has a polyphenol mechanism, has oxidation resistance, can inhibit peroxidation of membrane lipid, reduce generation of H: O, inhibit oxidation of low-density lipoprotein of a human body and the like, has the functions of resisting free radicals and oxidation, and can prevent diseases such as Parkinson's disease, viral hepatitis, Alzheimer's disease and the like. With the intensive research on resveratrol, resveratrol has been shown to have the pathological effects of protecting the cardiovascular system, regulating the blood lipid metabolism and inhibiting liver cirrhosis. In addition, the research shows that the resveratrol also has the anticancer effect, and can effectively inhibit the proliferation of cancer cells by acting with P450 cytochrome. However, resveratrol is poor in stability, has a solubility of only 23 μ g/ml, is easily decomposed by light, is easily oxidized, and undergoes cis-trans conversion under alkaline conditions, and thus, the exertion of its physiological activity is greatly limited. In addition, liposoluble resveratrol dissolves out at a lower rate in water, resulting in a lower absorption rate in vivo. In order to improve the bioavailability of resveratrol, the stability and the dissolution rate in water need to be improved. In recent years, with the deepening of the understanding of people on the health care function of human beings, the prevention of diseases such as tumors, cardiovascular diseases and the like, the research on resveratrol at home and abroad is greatly advanced.
Polyethylene glycol is a neutral and nontoxic high molecular polymer, and is one of the synthetic polymers approved by the U.S. food and drug administration and capable of being used for in vivo injection administration due to good biocompatibility and unique physicochemical properties. After the polyethylene glycol modifies the drug molecules, the solubility of the drug can be improved, and a space barrier can be generated around the drug molecules, so that the drug molecules are protected, and the stability of the drug is improved. However, since the chemical bond is generally stable, the drug release is limited due to the polymer-drug connection. Therefore, small molecule connecting arms are often used to connect the polymer and the drug in experiments, and the purpose is to reduce the steric hindrance of the polymer and realize the rapid release of the drug.
The targeted drugs are hot spots in the research of the current antitumor drugs, most of the common small-molecule targeted drugs are obtained by chemically modifying a small-molecule drug and a protein nano-carrier or a polymer nano-carrier, the preparation process is complex, the biocompatibility of the polymer nano-carrier is poor, and the influence on normal cells in vivo can be possibly caused.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a synthesis process of a tumor-targeted drug, which bonds micromolecular polyphenol-resveratrol with an anti-tumor effect and a high molecular polymer to form the targeted drug, simplifies the preparation process, and obtains polyethylene glycol-glycine-resveratrol with good biocompatibility and effectively treats tumors.
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 20-26 parts of N, N-dimethylformamide into a beaker, slowly adding 6-10 parts of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the beaker into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide after the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 10-16 parts of liquid polyethylene glycol, dissolving the N, N-dimethylformamide well, adding 3-5 parts of succinic anhydride and 1-3 parts of sodium hydride after complete dissolution, reacting in a water bath, evaporating the solvent under reduced pressure after the reaction is finished, adding 8-10 parts of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 16-20 parts of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 2-4 parts of thionyl chloride after complete dissolution, cooling to room temperature after reaction is finished, adding 10-16 parts of resveratrol and 10-14 parts of sodium hydroxide, continuing reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine: dissolving the polyethylene glycol carboxylic acid prepared in the step two in the treated N, N-dimethylformamide, after complete dissolution, adding 4-6 parts of N-hydroxysuccinimide and 6-8 parts of N, N-dicyclohexylcarbodiimide, cooling to room temperature, dissolving 2-4 parts of glycine in 6-8 parts of saturated sodium bicarbonate solution, then dropwise adding the mixture into the reaction solution obtained in the step three, continuing to react, after the reaction is finished, removing the solvent by rotary evaporation, adding 2-3 parts of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, adding the precipitate into deionized water to dissolve the precipitate, then adding the water solution into a dialysis bag for dialysis, and finally freeze-drying to obtain polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol: weighing polyethylene glycol-glycine in the fourth step, dissolving the polyethylene glycol-glycine in 3-5 parts of dichloromethane in ice bath, adding 2.5-4.5 parts of 4-dimethylaminopyridine and 2-4 parts of N, N-dicyclohexylcarbodiimide into the solution, stirring, adding 9-11 parts of resveratrol, keeping the reaction conditions unchanged, placing the solution into a dialysis bag for dialysis after the reaction is finished, and freeze-drying the aqueous solution after the dialysis to obtain polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: the polyethylene glycol-glycine-resveratrol is tested for particle size, solubility, light stability, acid-base stability, antioxidant performance and cytotoxicity.
Further, the purification of the reaction raw material N, N-dimethylformamide in the first step comprises the operation of removing water. The purposes of purification and dehydration are convenient to research, variable separation and improvement of the accuracy of experimental results;
further, the step two and the step three comprise a step of dialysis treatment. The dialysis treatment is a separation and purification technology for separating small molecules from biological macromolecules, so that later-stage research is facilitated.
Further, the reaction temperature in the fourth step was 50 ℃.
Further, the step four comprises the treatment steps of dissolution, evaporation, precipitation and dialysis.
Further, the fifth step comprises the processing steps of stirring, dialysis and freeze-drying.
Further, the preparation of the test sample in the sixth step is performed at room temperature of 20 ℃.
Further, the performance parameters of the sample in the seventh step include particle size, solubility, light stability, acid-base stability, antioxidant performance and cytotoxicity.
Further, the tests of particle size, solubility, photostability, acid-base stability, antioxidant property and cytotoxicity were performed at room temperature of 20 ℃.
The synthesis process of the tumor targeting drug has the advantages that: by regulating and controlling the composition and structure of the polymer, the light stability and acid-base stability of the prepared targeted drug polyethylene glycol-glycine-resveratrol are obviously improved, and the polyethylene glycol-glycine-resveratrol still has obvious antioxidant activity and further has obvious anticancer activity, so that the preparation method provides hope for treating cancer patients and has very important pharmacological significance.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to the specific embodiments. The described embodiments are only some embodiments of the invention, not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 20kg of three parts of N, N-dimethylformamide into a beaker, slowly adding 6kg of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the beaker into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide after the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 10kg of liquid polyethylene glycol and dissolved N, N-dimethylformamide, adding 3kg of succinic anhydride and 1kg of sodium hydride after complete dissolution, carrying out water bath reaction, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding 8kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 16kg of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 2kg of thionyl chloride after complete dissolution, cooling to room temperature after reaction, adding 10kg of resveratrol and 10kg of sodium hydroxide, continuing reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine: dissolving the polyethylene glycol carboxylic acid prepared in the step two in the treated N, N-dimethylformamide, after complete dissolution, adding 4kg of N-hydroxysuccinimide and 6kg of N, N-dicyclohexylcarbodiimide, cooling to room temperature, dissolving 2kg of glycine in 6kg of saturated sodium bicarbonate solution, then dropwise adding the mixture into the reaction solution obtained in the step three, continuing to react, after the reaction is finished, removing the solvent by rotary evaporation, adding 2kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, adding the precipitate into deionized water to dissolve the precipitate, then adding the aqueous solution into a dialysis bag for dialysis, and finally freeze-drying to obtain polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol: weighing polyethylene glycol-glycine in the fourth step, dissolving the polyethylene glycol-glycine in 3kg of ice-bath dichloromethane, adding 2.5kg of 4-dimethylaminopyridine and 2kg of N, N-dicyclohexylcarbodiimide into the solution, stirring, adding 9kg of resveratrol, keeping the reaction conditions unchanged, placing the solution into a dialysis bag for dialysis after the reaction is finished, and freeze-drying the aqueous solution after the dialysis to obtain polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: the polyethylene glycol-glycine-resveratrol is tested for particle size, solubility, light stability, acid-base stability, antioxidant performance and cytotoxicity.
Example 2
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 23kg of N, N-dimethylformamide into a beaker, slowly adding 8kg of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the preservative film into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide when the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 13kg of liquid polyethylene glycol and dissolved N, N-dimethylformamide, adding 4kg of succinic anhydride and 2kg of sodium hydride after complete dissolution, reacting in a water bath, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding 9kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 18kg of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 3kg of thionyl chloride after complete dissolution, cooling to room temperature after reaction, adding 13kg of resveratrol and 12kg of sodium hydroxide, continuing the reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine: dissolving the polyethylene glycol carboxylic acid prepared in the step two in the treated N, N-dimethylformamide, after complete dissolution, adding 5kg of N-hydroxysuccinimide and 7kg of N, N-dicyclohexylcarbodiimide, cooling to room temperature, dissolving 3kg of glycine in 7kg of saturated sodium bicarbonate solution, then dropwise adding the saturated sodium bicarbonate solution into the reaction solution obtained in the step three, continuing to react, after the reaction is finished, rotationally evaporating to remove the solvent, adding 2.5kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, adding the precipitate into deionized water to dissolve the precipitate, then adding the aqueous solution into a dialysis bag for dialysis, and finally freeze-drying to obtain polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol: weighing polyethylene glycol-glycine in the fourth step, dissolving the polyethylene glycol-glycine in 4kg of dichloromethane in an ice bath, adding 3.5kg of 4-dimethylaminopyridine and 3kg of N, N-dicyclohexylcarbodiimide into the solution, stirring, adding 10kg of resveratrol, keeping the reaction conditions unchanged, placing the solution into a dialysis bag for dialysis after the reaction is finished, and freeze-drying the aqueous solution after the dialysis to obtain polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: the polyethylene glycol-glycine-resveratrol is tested for particle size, solubility, light stability, acid-base stability, antioxidant performance and cytotoxicity.
Example 3
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 26kg of N, N-dimethylformamide into a beaker, slowly adding 10kg of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the preservative film into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide when the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 16kg of liquid polyethylene glycol dissolved N, N-dimethylformamide, adding 5kg of succinic anhydride and 3kg of sodium hydride after complete dissolution, carrying out water bath reaction, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding 10kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 20kg of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 4kg of thionyl chloride after complete dissolution, cooling to room temperature after reaction is finished, adding 16kg of resveratrol and 14kg of sodium hydroxide, continuing the reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine: dissolving the polyethylene glycol carboxylic acid prepared in the step two in the treated N, N-dimethylformamide, after complete dissolution, adding 6kg of N-hydroxysuccinimide and 8kg of N, N-dicyclohexylcarbodiimide, cooling to room temperature, dissolving 4kg of glycine in 8kg of saturated sodium bicarbonate solution, then dropwise adding the saturated sodium bicarbonate solution into the reaction solution obtained in the step three, continuing to react, after the reaction is finished, removing the solvent by rotary evaporation, adding 3kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, adding the precipitate into deionized water to dissolve the precipitate, then adding the aqueous solution into a dialysis bag for dialysis, and finally freeze-drying to obtain polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol: weighing polyethylene glycol-glycine in the fourth step, dissolving the polyethylene glycol-glycine in 5kg of ice-bath dichloromethane, adding 4.5kg of 4-dimethylaminopyridine and 4kg of N, N-dicyclohexylcarbodiimide into the solution, stirring, adding 11kg of resveratrol, keeping the reaction conditions unchanged, after the reaction is finished, putting the solution into a dialysis bag for dialysis treatment, and after the dialysis, carrying out freeze-drying treatment on the aqueous solution to obtain polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: the polyethylene glycol-glycine-resveratrol is tested for particle size, solubility, light stability, acid-base stability, antioxidant performance and cytotoxicity.
Example 4
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 23kg of N, N-dimethylformamide into a beaker, slowly adding 8kg of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the preservative film into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide when the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 13kg of liquid polyethylene glycol and dissolved N, N-dimethylformamide, adding 4kg of succinic anhydride and 2kg of sodium hydride after complete dissolution, reacting in a water bath, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding 9kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 18kg of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 2kg of thionyl chloride after complete dissolution, cooling to room temperature after reaction, adding 13kg of resveratrol and 12kg of sodium hydroxide, continuing the reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine: dissolving the polyethylene glycol carboxylic acid prepared in the step two in the treated N, N-dimethylformamide, after complete dissolution, adding 5kg of N-hydroxysuccinimide and 7kg of N, N-dicyclohexylcarbodiimide, cooling to room temperature, dissolving 3kg of glycine in 7kg of saturated sodium bicarbonate solution, then dropwise adding the saturated sodium bicarbonate solution into the reaction solution obtained in the step three, continuing to react, after the reaction is finished, rotationally evaporating to remove the solvent, adding 2.5kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, adding the precipitate into deionized water to dissolve the precipitate, then adding the aqueous solution into a dialysis bag for dialysis, and finally freeze-drying to obtain polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol: weighing polyethylene glycol-glycine in the fourth step, dissolving the polyethylene glycol-glycine in 4kg of dichloromethane in an ice bath, adding 3.5kg of 4-dimethylaminopyridine and 3kg of N, N-dicyclohexylcarbodiimide into the solution, stirring, adding 10kg of resveratrol, keeping the reaction conditions unchanged, placing the solution into a dialysis bag for dialysis after the reaction is finished, and freeze-drying the aqueous solution after the dialysis to obtain polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: the polyethylene glycol-glycine-resveratrol is tested for particle size, solubility, light stability, acid-base stability, antioxidant performance and cytotoxicity.
Example 5
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 23kg of N, N-dimethylformamide into a beaker, slowly adding 8kg of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the preservative film into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide when the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 13kg of liquid polyethylene glycol and dissolved N, N-dimethylformamide, adding 4kg of succinic anhydride and 2kg of sodium hydride after complete dissolution, reacting in a water bath, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding 9kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 18kg of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 1kg of thionyl chloride after complete dissolution, cooling to room temperature after reaction, adding 13kg of resveratrol and 12kg of sodium hydroxide, continuing the reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine: dissolving the polyethylene glycol carboxylic acid prepared in the step two in the treated N, N-dimethylformamide, after complete dissolution, adding 5kg of N-hydroxysuccinimide and 7kg of N, N-dicyclohexylcarbodiimide, cooling to room temperature, dissolving 3kg of glycine in 7kg of saturated sodium bicarbonate solution, then dropwise adding the saturated sodium bicarbonate solution into the reaction solution obtained in the step three, continuing to react, after the reaction is finished, rotationally evaporating to remove the solvent, adding 2.5kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, adding the precipitate into deionized water to dissolve the precipitate, then adding the aqueous solution into a dialysis bag for dialysis, and finally freeze-drying to obtain polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol: weighing polyethylene glycol-glycine in the fourth step, dissolving the polyethylene glycol-glycine in 4kg of dichloromethane in an ice bath, adding 3.5kg of 4-dimethylaminopyridine and 3kg of N, N-dicyclohexylcarbodiimide into the solution, stirring, adding 10kg of resveratrol, keeping the reaction conditions unchanged, placing the solution into a dialysis bag for dialysis after the reaction is finished, and freeze-drying the aqueous solution after the dialysis to obtain polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: testing the solubility, light stability, acid-base stability, oxidation resistance and cytotoxicity of the polyethylene glycol-glycine-resveratrol.
Comparative example 1
A process for synthesizing a tumor targeting drug comprises the following steps:
weighing 100mL of water in a beaker, weighing 100mg of resveratrol, gradually adding the resveratrol into the beaker, continuously stirring to fully dissolve the resveratrol until the resveratrol is saturated, weighing the mass of the remaining resveratrol, and calculating the mass of the dissolved resveratrol, namely the solubility.
Comparative example 2
A process for synthesizing a tumor targeting drug comprises the following steps:
the method comprises the following steps: purification and pretreatment: pouring 23kg of N, N-dimethylformamide into a beaker, slowly adding 8kg of calcium hydride, covering a layer of preservative film with a small hole on the beaker, standing, pouring the preservative film into a round-bottom flask, starting a rotary evaporator to discharge water, refluxing cooling water until no liquid is separated out, completely evaporating water and evaporating N, N-dimethylformamide when the temperature reaches 80 ℃ and is stable, filling the collected N, N-dimethylformamide into a reagent bottle, and storing the reagent bottle in a dryer with water-absorbing silica gel;
step two: synthesis of polyethylene glycol carboxylic acid: weighing 13kg of liquid polyethylene glycol and dissolved N, N-dimethylformamide, adding 4kg of succinic anhydride and 2kg of sodium hydride after complete dissolution, reacting in a water bath, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding 9kg of diethyl ether into the residue, cooling until the precipitate is completely separated out, filtering to obtain the precipitate, dissolving the precipitate with deionized water, putting the aqueous solution into a dialysis bag for dialysis, and freeze-drying the aqueous solution to obtain polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol: dissolving 18kg of polyethylene glycol carboxylic acid in the treated N, N-dimethylformamide, adding 3kg of thionyl chloride after complete dissolution, cooling to room temperature after reaction, adding 13kg of resveratrol and 12kg of sodium hydroxide, continuing reaction under the condition of keeping out of the sun, after the reaction is finished, putting the reaction solution into a dialysis bag for dialysis treatment, dialyzing and freeze-drying to obtain the polyethylene glycol-resveratrol.
The verification results are as follows:
weighing 100mL of water in a beaker, weighing 100mg of the product obtained in the examples 1-5, gradually adding the polyethylene glycol-glycine-resveratrol into the beaker, continuously stirring to fully dissolve the polyethylene glycol-glycine-resveratrol until the mixture is saturated, weighing the mass of the remaining polyethylene glycol-glycine-resveratrol, and calculating the mass of the dissolved polyethylene glycol-glycine-resveratrol, namely the solubility. The product of the polyethylene glycol-glycine-resveratrol obtained in examples 1 to 5 is irradiated under a solar light source, and then the change of the weight of the polyethylene glycol-glycine-resveratrol is measured to evaluate the light stability; dissolving polyethylene glycol-glycine-resveratrol in pH buffer solution with pH of 2, 6, 8, 10, 12, storing at 25 deg.C in dark place for 2 hr, detecting content of polyethylene glycol-glycine-resveratrol with photometer, and evaluating acid-base stability; a certain amount of DPPH is weighed and prepared into 0.04mg/mL DPPH solution by using absolute ethyl alcohol. Respectively taking 2mL of solutions with different concentrations (2, 4, 6 and 8mg/mL), adding 2mL of DPPH solution, mixing uniformly, standing at room temperature for 30min, and centrifuging at 5000r/min for 10 min. Taking the supernatant to measure the light absorption value at 517nm, using Vc as a positive control, calculating the clearance rate of DPPH free radicals, and obtaining the antioxidant performance; measuring 100mL of water in a beaker; weighing the resveratrol in the comparative example 1, placing the resveratrol under a solar light source for irradiation, measuring the weight change condition of the resveratrol, and evaluating the light stability; dissolving resveratrol in pH buffer solution with pH of 2, 6, 8, 10, and 12, storing at 25 deg.C in dark for 2 hr, detecting resveratrol content with photometer, and evaluating acid-base stability; a certain amount of DPPH is weighed and prepared into 0.04mg/mL DPPH solution by using absolute ethyl alcohol. Respectively taking 2mL of solutions with different concentrations (2, 4, 6 and 8mg/mL), adding 2mL of DPPH solution, mixing uniformly, standing at room temperature for 30min, and centrifuging at 5000r/min for 10 min. Taking the supernatant to measure the light absorption value at 517nm, using Vc as a positive control, calculating the clearance rate of DPPH free radicals, and obtaining the antioxidant performance; the results are shown in table 1:
TABLE 1
Irradiating the resveratrol in the comparative example 1 under a solar light source, measuring the weight change condition of the resveratrol, and evaluating the light stability; dissolving resveratrol in pH buffer solution with pH of 2, 6, 8, 10, and 12, storing at 25 deg.C in dark for 2 hr, detecting resveratrol content with photometer, and evaluating acid-base stability; a certain amount of DPPH is weighed and prepared into 0.04mg/mL DPPH solution by using absolute ethyl alcohol. Respectively taking 2mL of solutions with different concentrations (2, 4, 6 and 8mg/mL), adding 2mL of DPPH solution, mixing uniformly, standing at room temperature for 30min, and centrifuging at 5000r/min for 10 min. And (3) taking the supernatant to measure the light absorption value at 517nm, using Vc as a positive control, and calculating the clearance rate of DPPH free radicals to obtain the antioxidant performance.
Irradiating the polyethylene glycol-resveratrol in the comparative example 2 under a solar light source, measuring the weight change condition of the resveratrol, and evaluating the light stability; dissolving polyethylene glycol-resveratrol in pH buffer solution with pH of 2, 6, 8, 10, 12, storing at 25 deg.C in dark place for 2 hr, detecting resveratrol content with photometer, and evaluating acid-base stability; a certain amount of DPPH is weighed and prepared into 0.04mg/mL DPPH solution by using absolute ethyl alcohol. Respectively taking 2mL of solutions with different concentrations (2, 4, 6 and 8mg/mL), adding 2mL of DPPH solution, mixing uniformly, standing at room temperature for 30min, and centrifuging at 5000r/min for 10 min. And (3) taking the supernatant to measure the light absorption value at 517nm, using Vc as a positive control, and calculating the clearance rate of DPPH free radicals to obtain the antioxidant performance. The results are shown in table 2:
TABLE 2
As can be seen from tables 1 and 2: compared with the original product resveratrol, the solubility, the acid-base stability and the DPPH free radical clearance rate of the intermediate product polyethylene glycol-resveratrol and the final product polyethylene glycol-glycine-resveratrol are improved, and the solubility, the acid-base stability and the DPPH free radical clearance rate of the final product polyethylene glycol-glycine-resveratrol are the highest, so that the synthetic process is effective. Meanwhile, as shown in examples 1, 4 and 5, when the content of thionyl chloride is reduced while other components are kept unchanged, the solubility of polyethylene glycol-glycine-resveratrol is reduced, the content of resveratrol contained in the resveratrol is increased, namely, the acid-base stability is also improved, the clearance rate of DPPH free radicals is increased, namely, the oxidation resistance is improved, and the thionyl chloride is an effective component of the synthesis process of the tumor-targeted drug.
In conclusion, by regulating and controlling the composition and structure of the polymer, the light stability and acid-base stability of the prepared targeted drug polyethylene glycol-glycine-resveratrol are obviously improved, and the polyethylene glycol-glycine-resveratrol still has obvious antioxidant activity and further has obvious anticancer activity, so that the preparation method provides hope for treating cancer patients and has very important pharmacological significance.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (9)
1. A process for synthesizing a tumor targeting drug is characterized by comprising the following steps:
the method comprises the following steps: purifying and pretreating a reaction raw material N, N-dimethylformamide;
step two: synthesizing polyethylene glycol carboxylic acid;
step three: synthesizing polyethylene glycol-resveratrol;
step four: synthesizing polyethylene glycol-glycine;
step five: synthesizing polyethylene glycol-glycine-resveratrol;
step six: weighing polyethylene glycol-glycine-resveratrol;
step seven: the performance parameters of the samples were tested.
2. The process for synthesizing a tumor targeting drug according to claim 1, wherein the purification of the reaction raw material N, N-dimethylformamide in the first step comprises water removal.
3. The process for synthesizing a tumor targeting drug according to claim 1, wherein the step two and the step three comprise a step of dialysis treatment.
4. The process for synthesizing a tumor targeting drug according to claim 1, wherein the reaction temperature in the fourth step is 50 ℃.
5. The process for synthesizing a tumor targeting drug according to claim 1, wherein the step four comprises the steps of dissolution, evaporation, precipitation and dialysis.
6. The process for synthesizing a tumor targeting drug according to claim 1, wherein the step five comprises the processing steps of stirring, dialysis and freeze-drying.
7. The process for synthesizing a tumor targeting drug according to claim 1, wherein the preparation of the test sample in the sixth step is performed at 20 ℃ at room temperature.
8. The process for synthesizing a tumor targeting drug according to claim 1, wherein the performance parameters of the sample in the seventh step include particle size, solubility, light stability, acid-base stability, antioxidant property and cytotoxicity.
9. The process for synthesizing a tumor targeting drug according to claim 8, wherein the particle size, solubility, light stability, acid-base stability, oxidation resistance and cytotoxicity test is performed at 20 ℃ room temperature.
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