CN107522850B - Preparation method of water-soluble curcumin polymer - Google Patents
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Abstract
The invention relates to the field of drug synthesis, in particular to a preparation method of a water-soluble curcumin polymer; the method comprises the following steps: (1) mixing, (2) acidifying, (3) preparing a polymer; the method is simple and convenient to operate, the prepared curcumin polymer has excellent thermal stability, storage stability, controllable molecular weight and controllable degradation rate, the prepared curcumin polymer with excellent water solubility can be applied to oxidation resistance, virus resistance, liver protection, cholagogue, cancer resistance, blood fat reduction, anti-HIV, bacteriostasis and the like, compared with curcumin per se, the curcumin polymer not only greatly improves the stability and bioavailability of curcumin, but also obviously improves the cytotoxicity and anticancer capability of curcumin on cancer cells, and is expected to become a new anticancer drug.
Description
Technical Field
The invention relates to the field of drug synthesis, and particularly relates to a preparation method of a water-soluble curcumin polymer.
Background
Curcumin is a natural polyphenol natural product with novel structure and multiple biological activities, the basic skeleton of the curcumin is composed of a carbon chain with seven carbon atoms in the middle and aromatic rings connected to two ends of the carbon chain respectively, wherein the structures of 4-OH and 3-OCH 3 on the aromatic rings are active groups with strong antioxidant capacity. Curcumin is mainly separated from Zingiber plant, is also the main component of Curcuma rhizome with pharmacological activity, and has antibacterial, antioxidant, antiviral, liver protecting, gallbladder function promoting, anticancer, blood lipid reducing, and anti-HIV effects. At present, the method is widely applied to the fields of edible pigments, food additives and medicines. In recent years, curcumin is a natural product with small toxic and side effects, small molecular weight, low toxicity, low price and easy obtainment, is considered as an ideal anticancer drug and also becomes a hot spot for research of domestic and foreign scholars. With the gradual and intensive research on curcumin and derivatives thereof, the biological activity and the pharmacological activity of curcumin are gradually discovered and accepted, and phase i clinical trials have been carried out by the national cancer institute in the united states. The curcumin anticancer activity is continuously and comprehensively and deeply researched, so that the curcumin anticancer activity is expected to be developed into a novel, low-toxicity and high-efficiency anticancer medicament.
In recent years, curcumin has attracted attention of scholars at home and abroad due to the anti-tumor, immunoregulation, antioxidation and anti-atherosclerosis effects of curcumin, and has great development potential. However, curcumin has low bioavailability due to its poor water solubility, difficult absorption in vivo and rapid metabolism. In addition, curcumin rapidly decomposes under neutral or basic conditions and is insoluble in water under acidic conditions, which in turn makes it impractical for direct use as a pharmaceutical. In order to improve the bioavailability of curcumin and not influence the bioactivity of curcumin on a certain basis, the scholars HuadongTang and the like synthesize eight curcumin polymers by utilizing the condensation polymerization reaction of phenolic hydroxyl groups of curcumin and different monomers, wherein the polymer IV-1 shows very obvious bioactivity on tumor cells SKOV-3; scholars Youqingshen et al in US20120003177A1 disclose a method for preparing curcumin polymer, and hydrophilic group PEG is grafted on curcumin by the method to synthesize several curcumin polymers, so that the water solubility of curcumin is improved. The scholars Yufen gZhu and the like synthesize a new selenium-containing curcumin polymer IV-2 with the molecular weight of 6.1 x 104Da, and experiments show that the compound is stable, good in water solubility, injectable and has a good anti-hepatic fibrosis effect on mice. NoriyoshimatSUMI and the like utilize curcumin to respectively react with other two monomers, namely sebacoyl chloride and suberoyl chloride, through polycondensation to synthesize polymers IV-3 and IV-4 with different molecular weights, and two carbonyls of the curcumin in the obtained polymer are utilized to be matched with metal ruthenium to obtain a metal coordination polymer with high molecular weight, so that a new function is expected to be developed.
From the above reports, it is known that curcumin has poor water solubility, is not easily absorbed in vivo, is rapidly metabolized and has low bioavailability, but curcumin is a natural product which is cheap and easily available, has small toxic and side effects, small molecular weight and low toxicity, and has various biological activities such as oxidation resistance, virus resistance, liver protection, gallbladder function promotion, cancer resistance, blood fat reduction, anti-AIDS virus and bacteriostasis. In view of the excellent biological activity and pharmacological activity of curcumin, in order to improve the solubility of curcumin and the drug loading of curcumin as a medicine, the design and synthesis of curcumin macromolecular polymer has important economic significance and practical significance, and has positive promotion effect on medical development.
Disclosure of Invention
The invention provides a preparation method of a water-soluble curcumin polymer for solving the technical problems.
The method is realized by the following technical scheme:
a preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing purified curcumin and purified pyromellitic dianhydride in a mass ratio of 1: 1-5, adding a catalyst 1 into a 100ml three-mouth round-bottom bottle, adding the mixture into the three-mouth round-bottom bottle, uniformly stirring, adding triethylamine which is 2-6% of the mass of the curcumin, and stirring for reacting for 1-4 hours at normal temperature to obtain a material 1;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by using hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by using water, drying to obtain a crude product, recrystallizing the crude product by using chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, N '-dicyclohexylcarbodiimide, 4-N, N' -dimethylaminopyridine, material 2 and polyethylene glycol monomethyl ether into a dry 100ml three-neck round-bottom flask in sequence, stirring for 3 hours at normal temperature, carrying out suction filtration, washing the filtrate for 3-4 times by using a sodium carbonate solution with the content of 20-60%, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer.
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1: 1-5, adding a catalyst 1 into a 100ml three-mouth round-bottom bottle, adding the mixture into the three-mouth round-bottom bottle, uniformly stirring, adding triethylamine, and stirring at normal temperature for reaction for 1-4 hours to obtain a material 1;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by water, drying to obtain a crude product, recrystallizing the crude product by chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, triethylamine, tricarbonyl chloride, material 2 and polyethylene glycol monomethyl ether into a dry 100ml three-neck round-bottom flask in sequence, stirring and reacting for 1-4h in ice water bath (0 ℃), carrying out suction filtration, washing the filtrate for 3-4 times by using a sodium carbonate solution with the content of 20-60%, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer.
The purified curcumin is prepared by soaking curcumin in ethanol, stirring for 15-25 min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 15-25 min, filtering and drying.
The catalyst 1 in the step (2) is one of tetrahydrofuran and dichloromethane, wherein the ratio of the catalyst 1 to the curcumin is 10ml: 1-15 mg.
The adding ratio of the dichloromethane in the step (3) to the material 2 is 10ml: 1-15 mg.
The adding amount of the N, N' -dicyclohexylcarbodiimide is 3-10% of the mass of the material 2.
The addition amount of the 4-N, N' -dimethylamino pyridine is 0.2 to 0.6 percent of the mass of the material 2.
The addition amount of the triethylamine is 2-6% of the mass of the material 2.
The addition amount of the tricarbonyl chloride is 1-5% of the mass of the material 2.
The mass ratio of the material 2 to the polyethylene glycol monomethyl ether is 1: 1-5.
In conclusion, the beneficial effects of the invention are as follows: the method is simple and convenient to operate, the prepared curcumin polymer has excellent thermal stability, storage stability, controllable molecular weight and controllable degradation rate, the prepared curcumin polymer with excellent water solubility can be applied to oxidation resistance, virus resistance, liver protection, cholagogue, cancer resistance, blood fat reduction, anti-HIV, bacteriostasis and the like, compared with curcumin per se, the curcumin polymer not only greatly improves the stability and bioavailability of curcumin, but also obviously improves the cytotoxicity and anticancer capability of curcumin on cancer cells, and is expected to become a new anticancer drug.
Drawings
Fig. 1 is a graph showing the cytotoxic effect of curcumin polymer prepared in example 1 on cancer cells.
Detailed Description
The following is a detailed description of the embodiments of the present invention, but the present invention is not limited to these embodiments, and any modifications or substitutions in the basic spirit of the embodiments are included in the scope of the present invention as claimed in the claims.
Example 1
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1:1, adding tetrahydrofuran into a 100ml three-mouth round-bottom bottle, wherein the ratio of the tetrahydrofuran to the curcumin is 10ml:1mg, adding the mixture into a three-mouth round-bottom bottle, stirring uniformly, adding triethylamine which is 2% of the mass of the curcumin, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1; the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 15min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 15min, filtering and drying;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by using hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by using water, drying to obtain a crude product, recrystallizing the crude product by using chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, N '-dicyclohexylcarbodiimide in an amount which is 3% of the mass of material 2, 4-N, N' -dimethylaminopyridine in an amount which is 0.2% of the mass of material 2, and polyethylene glycol monomethyl ether in an amount which is 1 time of the mass of material 2 into a dry 100ml three-neck round-bottom flask in sequence, stirring for 3 hours at normal temperature, carrying out suction filtration, washing the filtrate for 3-4 times by using a sodium carbonate solution with the content of 20%, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer, wherein the adding ratio of the dichloromethane to the material 2 is 10ml:1 mg.
Example 2
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1:5, adding dichloromethane into a 100ml three-mouth round-bottom bottle, wherein the ratio of the dichloromethane to the curcumin is 10ml: 15mg, adding the mixture into a three-mouth round-bottom bottle, stirring uniformly, adding triethylamine which is 6% of the mass of the curcumin, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1; the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 25min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 25min, filtering and drying;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by using hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by using water, drying to obtain a crude product, recrystallizing the crude product by using chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, N '-dicyclohexylcarbodiimide in an amount which is 10 percent of the mass of material 2, 4-N, N' -dimethylaminopyridine in an amount which is 0.6 percent of the mass of material 2, and polyethylene glycol monomethyl ether in an amount which is 5 times of the mass of material 2 into a dry 100ml three-neck round-bottom flask in sequence, stirring for 3 hours at normal temperature, carrying out suction filtration, washing a filtrate for 3-4 times by using a sodium carbonate solution with the content of 60 percent, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer, wherein the adding ratio of the dichloromethane to the material 2 is 10ml: 15 mg.
Example 3
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1:3, adding tetrahydrofuran into a 100ml three-mouth round-bottom bottle, wherein the ratio of the tetrahydrofuran to the curcumin is 10ml: 8mg, adding the mixture into a three-mouth round-bottom bottle, stirring uniformly, adding triethylamine which is 4% of the mass of the curcumin, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1; the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 20min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 20min, filtering and drying;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by using hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by using water, drying to obtain a crude product, recrystallizing the crude product by using chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, N '-dicyclohexylcarbodiimide in an amount which is 6 percent of the mass of material 2, 4-N, N' -dimethylaminopyridine in an amount which is 0.4 percent of the mass of material 2, and polyethylene glycol monomethyl ether in an amount which is 3 times of the mass of material 2 into a dry 100ml three-neck round-bottom flask in sequence, stirring for 3 hours at normal temperature, carrying out suction filtration, washing a filtrate for 3-4 times by using a sodium carbonate solution with the content of 40 percent, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer, wherein the adding ratio of the dichloromethane to the material 2 is 10ml: 8 mg.
Example 4
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1:1, and adding tetrahydrofuran into a 100ml three-mouth round-bottom bottle, wherein the ratio of the tetrahydrofuran to the curcumin is 10ml: 15mg, adding the mixture into a three-mouth round-bottom bottle, stirring uniformly, adding triethylamine, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1; the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 15min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 25min, filtering and drying;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by water, drying to obtain a crude product, recrystallizing the crude product by chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, 2% of triethylamine by mass of material 2, 5% of tricarbonyl chloride by mass of material 2 and 1 time of polyethylene glycol monomethyl ether by mass of material 2 into a dry 100ml three-neck round-bottom flask in sequence, stirring and reacting for 1-4h in water bath at 0 ℃, performing suction filtration, washing a filtrate for 3-4 times by using a sodium carbonate solution with the content of 20% and then washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer, wherein the adding ratio of the dichloromethane to the material 2 is 10ml: 15 mg.
Example 5
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1:5, adding dichloromethane into a 100ml three-mouth round-bottom bottle, wherein the ratio of the dichloromethane to the curcumin is 10ml:1mg, adding the mixture into a three-mouth round-bottom bottle, stirring uniformly, adding triethylamine, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1; the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 15min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 25min, filtering and drying;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by water, drying to obtain a crude product, recrystallizing the crude product by chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, triethylamine 6% times of the mass of material 2, tricarbonyl chloride 1% of the mass of material 2 and polyethylene glycol monomethyl ether 5 times of the mass of material 2 into a dry 100ml three-neck round-bottom flask in sequence, stirring and reacting for 1-4h in a water bath at 0 ℃, performing suction filtration, washing a filtrate for 3-4 times by using a sodium carbonate solution with the content of 60%, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer, wherein the adding proportion of the dichloromethane to the material 2 is 10ml:1 mg.
Example 6
A preparation method of water-soluble curcumin polymer comprises the following steps:
(1) mixing materials: mixing the purified curcumin and the purified pyromellitic dianhydride in a mass ratio of 1:2, and adding tetrahydrofuran into a 100ml three-mouth round-bottom bottle, wherein the ratio of the tetrahydrofuran to the curcumin is 10ml: 10mg, adding the mixture into a three-mouth round-bottom bottle, stirring uniformly, adding triethylamine, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1; the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 20min, filtering and drying; the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 15min, filtering and drying;
(2) acidifying: adjusting the pH value of the material 1 to be 2-6 by hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by water, drying to obtain a crude product, recrystallizing the crude product by chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: adding dichloromethane, 5% of triethylamine by mass of material 2, 4% of tricarbonyl chloride by mass of material 2 and 3 times of polyethylene glycol monomethyl ether by mass of material 2 into a dry 100ml three-neck round-bottom flask in sequence, stirring and reacting for 1-4h in a water bath at 0 ℃, performing suction filtration, washing a filtrate for 3-4 times by using a sodium carbonate solution with the content of 50%, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the polymer, wherein the adding ratio of the dichloromethane to the curcumin is 10ml: 5 mg.
Taking the curcumin polymer (polymer 1 for short) prepared in example 1 as an example, detecting the cytotoxicity of the polymer 1 to cancer cells SKOV-3, OVCAR and MCF-7 by using an MTT (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide) method which is commonly used in the field and is used for detecting the survival and growth of the cells, treating the SKOV-3 cells, OVCAR cells and MCF-7 cells with the polymer 1 for 72 hours respectively, then culturing the cells in a blank culture medium for 24 hours, and calculating the survival rate of the cancer cells, wherein the survival rate is shown in figure 1, wherein 1 represents that the polymer 1 acts on the SKOV-3; 2 represents polymer 1 acting on OVCAR; 3 represents the action of Polymer 1 on MCF-7; 4 indicates that curcumin acts on SKOV-3.
The detection principle of the MTT method is as follows: succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline Formazan (Formazan) and deposit in cells, while dead cells do not have this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at 490nm wavelength by enzyme linked immunosorbent assay, which can indirectly reflect the number of living cells, and the amount of MTT crystal formed is directly proportional to the number of cells in a certain range of cell number.
As can be seen from fig. 1: the curcumin polymer prepared in the embodiment 1 has higher cytotoxicity to SKOV-3, OVCAR and MCF-7 than curcumin, and the curcumin polymer greatly improves the effect of the curcumin on cancer cells and is expected to realize clinical application.
In the in vivo experiment in mice using the polymer synthesized in example 1 as an example, the injection dose of the drug was 100mg/kg, and 48 hours later, the tumor weight of the mice injected with the curcumin polymer prepared in example 1 was 0.3523g, while the tumor weight of the mice injected with the Phosphate Buffer Solution (PBS) of the control was 1.2532g, which demonstrated that the curcumin polymer prepared in example 1 had an extremely high ability to inhibit tumor growth.
Claims (1)
1. A preparation method of a water-soluble curcumin polymer is characterized by comprising the following steps:
(1) mixing materials: mixing purified curcumin and purified pyromellitic dianhydride in a mass ratio of 1:1, adding tetrahydrofuran into a 100ml three-mouth round-bottom bottle, wherein the ratio of the tetrahydrofuran to the curcumin is 10ml:1mg, adding the mixture into the three-mouth round-bottom bottle, uniformly stirring, adding triethylamine accounting for 2% of the mass of the curcumin, and stirring and reacting for 1-4 hours at normal temperature to obtain a material 1;
(2) acidifying: adjusting the pH value of the material 1 to 2-6 by hydrochloric acid, stirring in a water bath until a yellow solid is separated out, performing suction filtration, washing a filter cake to be neutral by water, drying to obtain a crude product, recrystallizing the crude product by chloroform, drying and weighing to obtain a light yellow solid, and counting as a material 2;
(3) preparation of the polymer: sequentially adding dichloromethane, N '-dicyclohexylcarbodiimide in an amount which is 3% of the mass of material 2, 4-N, N' -dimethylaminopyridine in an amount which is 0.2% of the mass of material 2, and polyethylene glycol monomethyl ether in an amount which is 1% of the mass of material 2 into a dry 100ml three-neck round-bottom flask, stirring for 3 hours at normal temperature, carrying out suction filtration, washing the filtrate for 3-4 times by using a sodium carbonate solution with the content of 20%, washing the filtrate to be neutral by using a saturated sodium chloride solution, drying the filtrate by using anhydrous magnesium sulfate, and evaporating the solvent to obtain the water-soluble curcumin polymer;
the purified curcumin is prepared by soaking curcumin in ethanol, stirring for 15min, filtering and drying;
the purified pyromellitic dianhydride is prepared by soaking pyromellitic dianhydride in an acetic anhydride solution, stirring for 15min, filtering and drying;
wherein the addition ratio of dichloromethane to material 2 is 10ml to 1 mg.
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