CN119504664A - Eicosapentaenoic acid derivatives, preparation methods and applications thereof, and drugs for preventing and treating nervous system diseases - Google Patents
Eicosapentaenoic acid derivatives, preparation methods and applications thereof, and drugs for preventing and treating nervous system diseases Download PDFInfo
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Abstract
本发明提供了二十碳五烯酸衍生物及其制备方法和应用、防治神经系统疾病药物，属于医药技术领域。本发明提供的二十碳五烯酸衍生物具有式I所示结构，其为二十碳五烯酸（EPA）的酯类衍生物，脂溶性强，能够实现EPA药效的提升。本发明药理实验表明EPA衍生物具有比EPA更好的神经细胞保护作用，有望拓展EPA的药用价值。式I。
The present invention provides eicosapentaenoic acid derivatives and preparation methods and applications thereof, and drugs for preventing and treating nervous system diseases, and belongs to the field of medical technology. The eicosapentaenoic acid derivatives provided by the present invention have a structure shown in formula I, which is an ester derivative of eicosapentaenoic acid (EPA), has strong fat solubility, and can achieve the improvement of EPA efficacy. The pharmacological experiments of the present invention show that the EPA derivatives have better nerve cell protection than EPA, and are expected to expand the medicinal value of EPA. Formula I.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an eicosapentaenoic acid derivative, a preparation method and application thereof, and a medicine for preventing and treating nervous system diseases.
Background
Eicosapentaenoic acid (EPA) is a special omega-3 fatty acid and plays multiple roles of regulating metabolism, anti-inflammatory, anti-oxidation and the like in organisms. EPA has been shown to be involved in the formation of cellular membranes, to affect cell signaling, and to exert anti-inflammatory, antioxidant, anti-apoptotic effects by modulating gene expression, affecting metabolic pathways, and the like. These biological properties make EPA show great potential in research in various fields such as cardiovascular diseases and inflammatory diseases.
But EPA has difficulty in penetrating directly into cells through tissue barrier, resulting in insufficient bioactivity.
Disclosure of Invention
The invention aims to provide an eicosapentaenoic acid derivative, a preparation method and application thereof, and a medicament for preventing and treating nervous system diseases.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an eicosapentaenoic acid derivative which has a structure shown in a formula I:
formula I.
The invention provides a preparation method of an eicosapentaenoic acid derivative, which comprises the following steps:
Mixing eicosapentaenoic acid, an activating agent and an organic solvent, and performing activation treatment to obtain an activated feed liquid;
and mixing the activated feed liquid with tetrahydro-2-furanmethanol, and performing esterification reaction to obtain the eicosapentaenoic acid derivative with the structure shown in the formula I.
Preferably, the activating agent comprises N, N-diisopropylethylamine, 1-hydroxybenzotriazole and (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, wherein the activating treatment temperature is 10-40 ℃ and the activating treatment time is 20-40 min.
Preferably, the molar ratio of the eicosapentaenoic acid to the tetrahydro-2-furanmethanol is 1:1-1.5.
Preferably, the temperature of the esterification reaction is 10-40 ℃ and the time is 1-3 h.
The invention provides application of the eicosapentaenoic acid derivative in preparing medicines for preventing and treating nervous system diseases.
Preferably, the neurological disease comprises a neurodegenerative disease.
Preferably, the neurodegenerative disease comprises alzheimer's disease or parkinson's disease.
The invention provides a medicine for preventing and treating nervous system diseases, and an active component comprises eicosapentaenoic acid derivatives according to the technical scheme.
Preferably, the dosage form of the medicament for preventing and treating the nervous system diseases comprises injection, pill or capsule.
The invention provides an eicosapentaenoic acid derivative with a structure shown in a formula I. The eicosapentaenoic acid derivative provided by the invention is an ester derivative of eicosapentaenoic acid, has strong fat solubility and can realize improvement of EPA drug effect. The pharmacological experiment shows that the EPA derivative has better nerve cell protection effect than EPA, and is hopeful to expand the medicinal value of EPA.
Drawings
FIG. 1 is a synthetic route diagram of EPA derivatives;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of EPA derivatives;
FIG. 3 is a graph showing the effect of cell viability on HT22 measured by continued culture for 24H after treatment with different concentrations of H 2O2 for 4H after cell culture for 24H;
FIG. 4 is a graph showing the results of the protection of HT22 cells against oxidative damage models by varying concentrations of EPA;
FIG. 5 is a graph showing the results of protection of HT22 cells against oxidative damage models by EPA derivatives at various concentrations.
Detailed Description
The invention provides an eicosapentaenoic acid derivative which has a structure shown in a formula I:
formula I.
EPA has a wide range of physiological activities, but is highly polar, and it is difficult to penetrate the hydrophobic phospholipid layer into cells, resulting in insufficient biological activity. According to the invention, through structural transformation of EPA, a novel EPA derivative (particularly an ester derivative of EPA) is developed and designed, the EPA derivative has strong fat solubility and good absorption, can enter cells in a targeting way to play a role, has higher bioavailability, can realize the improvement of EPA drug effect, such as improving the metabolism and the function of neurons, promoting the regeneration and the repair of nerves, and has a certain prevention and treatment effect on nervous system diseases. The pharmacological experiment shows that the EPA derivative has better nerve cell protection effect than EPA, and is hopeful to expand the medicinal value of EPA.
The invention provides a preparation method of an eicosapentaenoic acid derivative, which comprises the following steps:
Mixing eicosapentaenoic acid, an activating agent and an organic solvent, and performing activation treatment to obtain an activated feed liquid;
and mixing the activated feed liquid with tetrahydro-2-furanmethanol, and performing esterification reaction to obtain the eicosapentaenoic acid derivative with the structure shown in the formula I.
In the present invention, unless otherwise specified, all materials are commercially available or prepared by methods well known to those skilled in the art.
The invention mixes eicosapentaenoic acid, activator and organic solvent to activate and obtain activated feed liquid. As one embodiment of the invention, the activator may include N, N-Diisopropylethylamine (DIPEA), 1-Hydroxybenzotriazole (HOBT) and (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), the molar ratio of eicosapentaenoic acid, DIPEA, HOBT and EDC. HCl may be 1:2.5-3.5:1-2:1-2, and may be 1:3:1.5:1.5.
According to one embodiment of the invention, the eicosapentaenoic acid is dissolved in an organic solvent, and then DIPEA, HOBT and EDC and HCl are added for activation treatment, wherein the temperature of the activation treatment can be 10-40 ℃, the temperature can be room temperature (25 ℃), the time can be 20-40 min, the time can be 30min, and the activation treatment can be performed under the stirring condition.
After the activation treatment, the invention directly mixes the obtained activation feed liquid with tetrahydro-2-furanmethanol without any post treatment, and carries out esterification reaction to obtain the eicosapentaenoic acid derivative with the structure shown in the formula I. As an embodiment of the invention, the molar ratio of eicosapentaenoic acid to tetrahydro-2-furanmethanol may be 1:1-1.5, and may be specifically 1:1.2. According to the method, the temperature of the esterification reaction can be 10-40 ℃, specifically can be room temperature, the time can be 1-3 h, specifically can be 2h, and the esterification reaction can be carried out under the stirring condition. The reaction was monitored by TLC in the examples of the present invention.
As an embodiment of the present invention, after the esterification reaction, water may be added to the obtained product system, the solution is separated, the aqueous phase is extracted with dichloromethane, the organic phase is collected, the organic phase is washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, filtered, the solvent in the filtrate is spin-dried, and the solvent is separated by a silica gel column (the eluent may be petroleum ether: ethyl acetate=1:10 by volume ratio), thereby obtaining the eicosapentaenoic acid derivative having the structure shown in formula I.
The invention provides application of the eicosapentaenoic acid derivative in preparing medicines for preventing and treating nervous system diseases. The EPA derivative provided by the invention has strong fat solubility and higher bioavailability, and can realize improvement of EPA drug effect. In the test examples of the invention, specifically, an HT22 cell oxidative damage model is constructed through H 2O2 induction, and then the EPA derivative and EPA are studied for cytoprotective effect, so that the EPA derivative has stronger therapeutic potential than EPA in relieving the H 2O2 induced HT22 cell oxidative damage.
As an embodiment of the present invention, the nervous system disease may include a neurodegenerative disease, and the neurodegenerative disease may include alzheimer's disease or parkinson's disease.
The medicament for preventing and treating the nervous system diseases comprises the eicosapentaenoic acid derivative (namely, taken as an active ingredient) and pharmaceutically acceptable auxiliary materials. The specific types of the pharmaceutically acceptable auxiliary materials are not particularly limited, and pharmaceutically acceptable auxiliary materials of the types well known to those skilled in the art can be adopted. As an embodiment of the present invention, the dosage form of the drug for preventing and treating nervous system diseases may include injection, pill or capsule.
The invention provides a medicine for preventing and treating nervous system diseases, and an active component comprises eicosapentaenoic acid derivatives according to the technical scheme. As an embodiment of the present invention, the composition and dosage form of the drug for preventing and treating nervous system diseases may be consistent with the above technical solutions, and will not be described herein.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The starting materials used in the examples below are commercially available as known to those skilled in the art or are prepared by methods known to those skilled in the art.
The reagents used in the following test examples include hippocampal neuron HT22 cell line (Saibutz Biotechnology Co., ltd.), EPA derivative (prepared in example 1), EPA (MedChemExpress), fetal bovine serum (Thermo FISHER SCIENTIFI Co., ltd.), DMEM high sugar medium (gibco), a mixture of penicillin and streptomycin (Solarbio), 0.25% trypsin (gibco), absolute ethanol (Guangdong Guangshi optical technologies Co., ltd.), PBS powder (Biosharp), CCK-8 kit (Japanese homonym).
The experimental apparatus used in the following test examples included a carbon dioxide incubator (Thermo FISHER SCIENTIFI company), a multifunctional enzyme-labeled instrument (BioTek company, usa), a constant temperature water bath (beijing medical equipment factory), and a microscope (OLYMPUS).
Other reagents and apparatus not specifically described are available directly.
Example 1
FIG. 1 is a synthetic scheme of EPA derivatives, and a method for producing EPA derivatives will be described in detail with reference to FIG. 1.
Eicosapentaenoic acid (EPA, 2.76g,9.13 mmol) was dissolved in 15mL of N, N-Dimethylformamide (DMF), N-diisopropylethylamine (DIPEA, 3.54g,3 eq.) was added at room temperature, 1-hydroxybenzotriazole (HOBT, 1.85g,1.5 eq.) was combined with (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl,2.63g,1.5 eq.) and stirred at room temperature for 30min, then tetrahydro-2-furanmethanol (1.12 g,11mmol,1.2 eq.) was added, stirring at room temperature for 2h, TLC was monitored to monitor the reaction, 30mL of water was added to the resultant product system, the aqueous phase was extracted three times with methylene chloride, the organic phase was washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, the solvent was spin-dried, and separated by silica gel column (in volume ratio, eluting solvent used was petroleum ethyl acetate=1:10), and the specific EPA-2-hydrofuran derivative was obtained as shown in FIG. 2.
Test example 1
1. Experimental method
(1) Culture process of HT22 cells
1.1, Carrying out recovery operation on HT22 cells, injecting 5mL of DMEM high-sugar complete culture medium into a culture dish with the diameter of 60mm, taking 10% fetal bovine serum as a nutrition source in advance, adding 1% of a mixture of green streptomycin to ensure a sterile culture environment, uniformly inoculating the HT22 cells into the culture dish, placing the inoculated culture dish into a constant-temperature incubator with the concentration of 5% at the temperature of 37 ℃ C, CO 2, and carrying out primary culture for 24 hours to promote the adherence and primary proliferation of the cells.
1.2, When the cell is observed to grow on the wall of the bottom of the culture dish to 80-90% coverage, performing cell passage operation to maintain proper cell density. Prior to this, the required media, PBS buffer and trypsin solution were pre-warmed to 37 ℃ to ensure temperature consistency during the operation. After removal of the old medium, the cell surface was gently rinsed with pre-warmed PBS buffer to remove residual medium and non-adherent impurities. Subsequently, 1mL of trypsin solution was added to the culture dish, and the dish was gently shaken to uniformly cover the cell layer with trypsin, and then the dish was put back into a 37 ℃ incubator for digestion for 1min to effectively isolate adherent cells. Immediately after digestion was completed, 2mL of fresh DMEM high sugar complete medium was added to neutralize trypsin activity and cells were separated from the bottom of the dish by gentle pipetting to form a cell suspension.
1.3 Transfer the cell suspension to a 15mL centrifuge tube and treat it at 24℃for 3min under 1000 Xg centrifugation to pellet the cells at the bottom of the tube. Subsequently, the supernatant was carefully removed and 2mL of fresh DMEM high sugar complete medium was added to the centrifuge tube, again gently swirled to form a uniform cell suspension. Finally, 1mL of the cell suspension was aspirated from the suspension, re-inoculated into a new 60mm diameter petri dish, and supplemented with 5mL of DMEM high sugar complete medium, and continued to be placed in a 37 ℃ incubator for subsequent cultivation.
(2) Construction and evaluation of HT22 cell oxidative damage model
2.1 Gradient treatment of HT22 cells with H 2O2 concentration
To investigate the effect of different concentrations of H 2O2 on oxidative damage to HT22 cells, HT22 cells in the logarithmic growth phase and in good condition were selected for this experiment and precisely seeded in 96-well plates at a density of 3.5X10. 10 3 cells per well. After 24H of cell attachment and stabilization, a liquid change operation was performed to expose each group of cells to DMEM high sugar complete medium containing different final concentrations of H 2O2 (0, 200 μm, 400 μm, 600 μm), each group was provided with 4 duplicate wells to enhance the reliability of experimental results. Subsequently, the well plate was placed in a constant temperature incubator at 37℃ C, CO 2% strength for 4 hours in the dark to simulate an in vitro oxidative stress environment. After the end of the culture, all the old medium was removed and replaced with fresh DMEM high sugar complete medium, and the extent of oxidative damage of the cells was detected after further culture for 24 hours.
2.2 Cell viability assay based on CCK-8 method
Based on the experiment of 2.1, the survival rate of each group of cells was quantitatively evaluated by CCK-8 method after the predetermined incubation time was over. First, the old medium in the well plate was removed, and 100. Mu.L of DMEM high-sugar basal medium was added to each well in a mixture with 10. Mu.L of CCK-8 solution. At the same time, a blank (i.e., medium alone with CCK-8 solution, without cells) was set up to correct for background absorbance values. Subsequently, the well plate was incubated under the same conditions in the absence of light for 2h to allow CCK-8 to react well with dehydrogenases in living cells, producing a detectable color change. After the incubation, absorbance values (OD) of each well were measured at wavelengths of 450nm and 610nm, respectively, using a microplate reader, and interference of nonspecific absorption was eliminated by calculating differences (OD 450nm-OD610 nm). The calculation formula of the cell viability is [ (experimental hole OD value-blank hole OD value)/(control hole OD value-blank hole OD value) ]multipliedby 100%. Wherein, the experimental wells represent the mixed solution of HT22 cells and CCK-8 in each group after administration, the control wells are mixed solution of normal HT22 cells and CCK-8 without any treatment, and the blank wells are solution containing only culture medium and CCK-8 for eliminating background interference. By comparing the cell survival rates under the treatment of different H 2O2 concentrations, the proper oxidative damage condition can be screened out, and a reliable basis is provided for the subsequent deep research.
(3) HT22 model protective effect concentration screening of EPA and EPA derivatives on H 2O2 injury
3.1, H 2O2 concentration determination and Experimental grouping
Based on the experimental results of 2.2, the appropriate concentrations required for the preparation of the model of H 2O2 -induced oxidative damage to HT22 cells were determined. The experimental groupings were set as follows:
Normal Control group (Control) cultured with DMEM high sugar complete medium;
Model group (H 2O2 group) co-cultured with DMEM high-sugar complete medium at 400 μ M H 2O2;
The experimental groups were set up with multiple EPA and EPA derivative concentration gradients (0. Mu.M, 10. Mu.M, 20. Mu.M, 40. Mu.M, 80. Mu.M), each concentration group being used in combination with 400. Mu. M H 2O2 and DMEM high-sugar complete medium.
3.2 Determination of effective drug administration concentration of EPA and EPA derivatives
HT22 cells in the logarithmic growth phase and in good growth state were selected and precisely seeded in 96-well plates at a density of 3.5X10 3 cells per well. After 24h of cell wall-attached culture, the culture medium was changed, and each group of cells was exposed to a complete medium containing EPA and EPA derivatives at different final concentrations (0. Mu.M, 10. Mu.M, 20. Mu.M, 40. Mu.M, 80. Mu.M), and EPA derivatives were prepared by dissolving in absolute ethanol in advance, and the final concentration of absolute ethanol was <0.1%. After continuous culture for 24 hours, old medium was withdrawn, and DMEM high sugar complete medium containing 400 μ M H 2O2 was added to each group, while normal control group (DMEM high sugar complete medium alone) was established. 4 compound holes are arranged in each group, and the culture is carried out for 4 hours in a constant temperature incubator with the temperature of 37℃, CO 2 and the concentration of 5 percent in a dark place. Subsequently, all media was removed, replaced with fresh DMEM high sugar complete media, and after further incubation for 24 hours CCK-8 cell viability assays were performed following the standard procedure described in 2.2.
2. Experimental results
By adopting an H 2O2 induction strategy, the experiment successfully constructs an HT22 cell oxidative damage model, and after systematic evaluation, the optimal condition for constructing the model is established by treating 400 mu M H 2O2 for 4 hours. Subsequently, in the experimental group, HT22 cells were previously treated with EPA and EPA derivatives at different concentration gradients for 24H, then exposed to H 2O2 for 4H oxidative damage treatment, and replaced with fresh medium for further incubation for 24H. Experimental results show that EPA showed unexpected inhibition of cell viability at low concentration ranges (10 μm, 20 μm) and protective trend at higher concentrations (40 μm, 80 μm), but this effect was not statistically significant. In contrast, EPA derivatives showed stronger protective effects on cells with increasing concentration, especially at a concentration of 80. Mu.M, which was statistically significant (P < 0.01). The following is a detailed description.
(1) Effect of different concentrations of H 2O2 on HT22 cell viability
The effect of different concentrations of H 2O2 on HT22 cell viability was systematically evaluated using the CCK-8 method. Fig. 3 is a graph showing the effect of the cell viability assay on HT22 after 24H of cell culture and 4H of treatment with H 2O2 at different concentrations (P <0.01, P <0.001, P <0.0001 compared to the control group), in which the viability of HT22 cells significantly decreased with increasing H 2O2 concentration. Specifically, 200 μ M H 2O2 treatment has resulted in significant inhibition of cell viability (P < 0.01), whereas 400 μ M H 2O2 has a more pronounced inhibitory effect (P < 0.001), 600 μ M H 2O2 further exacerbates this trend (P < 0.0001). Based on the above results, the experiment selects 400 μ M H 2O2 treated for 4h as standard model conditions for inducing oxidative damage to HT22 nerve cells.
(2) Vitality impact of different concentrations of EPA on HT22 oxidative damage model
The effect of EPA at different concentrations on the viability of HT22 oxidative damage model cells was examined using CCK-8 method. Fig. 4 is a graph showing the results of the protection of HT22 cells from oxidative damage models by EPA at different concentrations (P <0.0001 compared to model group), and it is clear from fig. 4 that EPA does not show significant protection at 10 μm and 20 μm concentrations compared to H 2O2 model group, and that EPA gradually enhances the protection of cells at 40 μm and 80 μm concentrations, but has not yet reached statistical significance.
(3) Effect of different concentrations of EPA derivatives on the viability of HT22 oxidative damage models
The effect of various concentrations of EPA derivatives on cell viability in the model of HT22 oxidative damage was further assessed. Fig. 5 is a graph showing the results of protection of HT22 cell oxidative damage models by EPA derivatives at different concentrations (P <0.01, P <0.001 compared to model group), and as seen from fig. 5, EPA derivatives at each concentration group (10 μm, 20 μm, 40 μm, 80 μm) showed enhanced cytoprotection with increasing concentration compared to H 2O2 model group. In particular, the 80 μm EPA derivative group showed significant statistical differences (P < 0.01), indicating a stronger protective effect against H 2O2 -induced oxidative damage of HT22 cells.
From the above results, the present invention successfully constructs an oxidative damage model of HT22 cells by H 2O2 induction, and a significant decrease in cell viability was observed. After determining 400 mu M H 2O2 treatment for 4 hours as the optimal modeling conditions, the cytoprotective effect of EPA and EPA derivatives under pretreatment conditions was further investigated. Experimental results show that EPA shows some protective trend at high concentrations, but not statistical significance. In contrast, EPA derivatives significantly enhanced cytoprotective effects with increasing concentration, particularly exhibited significant statistical differences at 80 μm concentration, suggesting that EPA derivatives have a greater therapeutic potential in alleviating H 2O2 -induced oxidative damage to HT22 cells than EPA. This discovery provides a new concept and direction for the treatment of related neurological diseases such as neurodegenerative diseases.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. An eicosapentaenoic acid derivative characterized by having a structure represented by formula I:
formula I.
2. A process for the preparation of eicosapentaenoic acid derivatives as claimed in claim 1, characterised in that it comprises the steps of:
Mixing eicosapentaenoic acid, an activating agent and an organic solvent, and performing activation treatment to obtain an activated feed liquid;
and mixing the activated feed liquid with tetrahydro-2-furanmethanol, and performing esterification reaction to obtain the eicosapentaenoic acid derivative with the structure shown in the formula I.
3. The preparation method of claim 2, wherein the activating agent comprises N, N-diisopropylethylamine, 1-hydroxybenzotriazole and (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the activating treatment is performed at a temperature of 10-40 ℃ for 20-40 min.
4. The preparation method according to claim 2, wherein the molar ratio of eicosapentaenoic acid to tetrahydro-2-furanmethanol is 1:1-1.5.
5. The preparation method according to claim 2, wherein the esterification reaction is carried out at a temperature of 10-40 ℃ for a time of 1-3 hours.
6. Use of the eicosapentaenoic acid derivative of claim 1 in the preparation of a medicament for the prevention and treatment of neurological diseases.
7. The use according to claim 6, wherein the neurological disease comprises a neurodegenerative disease.
8. The use according to claim 7, wherein the neurodegenerative disease comprises alzheimer's disease or parkinson's disease.
9. A medicament for preventing and treating nervous system diseases, characterized in that an active ingredient comprises the eicosapentaenoic acid derivative as claimed in claim 1.
10. The medicament for preventing and treating nervous system diseases according to claim 9, wherein the dosage form of the medicament for preventing and treating nervous system diseases comprises injection, pill or capsule.
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