CN111333694B - Application of hederagenin derivative in medicine for resisting myocardial anoxia reoxygenation injury - Google Patents
Application of hederagenin derivative in medicine for resisting myocardial anoxia reoxygenation injury Download PDFInfo
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- CN111333694B CN111333694B CN202010347919.3A CN202010347919A CN111333694B CN 111333694 B CN111333694 B CN 111333694B CN 202010347919 A CN202010347919 A CN 202010347919A CN 111333694 B CN111333694 B CN 111333694B
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- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention relates to the technical field of medicaments, in particular to application of hederagenin derivatives in preparing a medicament for resisting myocardial ischemia reperfusion injury and anoxia reoxygenation injury, wherein the compounds are stable in solution and have obvious protective activity for resisting myocardial anoxia reoxygenation injury, especially myocardial ischemia reperfusion injury, myocardial muscle can be better protected from anoxia reoxygenation injury at 80 mu mol/L, and the derivatives have stronger pharmacological activity than that of parent nucleus hederagenin under the same dosage, thereby providing a new choice for treating the protection for resisting myocardial anoxia reoxygenation injury and myocardial ischemia reperfusion injury.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to application of hederagenin derivatives in preparation of a drug for resisting myocardial anoxia reoxygenation injury.
Background
Cardiovascular diseases are a series of diseases involving the circulatory system. Coronary heart disease, heart failure, acute myocardial infarction and the like are common cardiovascular diseases, and pathogenic mechanisms are all related to myocardial cell injury caused by myocardial ischemia-reperfusion. Researches indicate that the pathogenesis of the cardiovascular disease is complex, and the medicaments for treating the cardiovascular disease on the market have the defects of weak activity, low selectivity and large side effect, so that the medicaments have certain limitations and cannot fundamentally control the disease condition. Therapeutic agents for myocardial ischemia reperfusion injury are well known in prior studies. Among the many known therapeutic agents, the more effective ones are rosiglitazone, simvastatin, amiloride, trimetazidine, and the like. However, the medicines have the defects of weak specificity, low curative effect, obvious tolerance after long-term taking and the like. This prevents effective treatment of myocardial ischemia reperfusion injury diseases. At present, researchers at home and abroad find that the effective components of common medicinal materials such as astragalus, coptis, rhodiola and the like have the functions of inhibiting myocardial cell death, promoting angiogenesis, improving cardiac function and protecting cardiovascular system. Therefore, the search for cardiovascular treatment drugs with the advantages of strong selectivity, suitability for long-term administration, small side effect and the like from traditional Chinese medicines becomes a hot point for the research of medical researchers at home and abroad.
Hederagenin is an oleanane type pentacyclic triterpene compound, is distributed in various natural plants such as radix Dipsaci, flos Lonicerae, caulis Akebiae, Lonicera fulvidraco, etc., and has pharmacological effects of resisting cancer and HBV, treating hyperlipemia, cardiovascular disease, etc. In recent years, hederagenin is increasingly emphasized by people particularly with the characteristics of low toxicity and high efficiency and diversified cardiovascular disease resistant action mechanisms, and shows great clinical application potential and good application prospect. However, the problem that the preparation of the preparation is difficult and the in vivo bioavailability is low due to the fact that the hederagenin is difficult to dissolve in water is solved, so that the solubility of the slightly soluble hederagenin is improved by modifying the structure of the hederagenin, the effect of resisting cardiovascular diseases is further improved, the bioavailability of the slightly soluble hederagenin is effectively improved, and the slightly soluble hederagenin becomes a hotspot and a difficulty for research of researchers increasingly.
Before the method is completed, the hederagenin structure is modified, the structural modification is mainly focused on carboxyl at C-28 position, and hydroxyl at C-3 and C-23 position is modified to synthesize ester derivatives, amide derivatives and azole derivatives, and the activity is mainly focused on anti-tumor, anti-depression, anti-inflammation, anti-diabetes and the like. On the basis of earlier-stage research, the subject group discovers that the compound can obviously improve the solubility of hederagenin, and the physicochemical property of the compound is stable; in addition, compared with the mother nucleus, the activity is more obvious. The hederagenin derivative synthesized by the inventor has the main advantages that:
1) the derivative can further improve the solubility of hederagenin, and has better advantages in the aspects of physicochemical property and pharmacy;
2) the protective effect of the derivative on myocardial ischemia reperfusion injury is obviously better than that of a hederagenin parent body, and the derivative is a potential high-efficiency low-toxicity candidate drug for resisting myocardial ischemia.
Before the completion of the invention, no report on the anti-myocardial ischemia of the hederagenin derivative is reported in the literature, and no report on the application of the hederagenin derivative in the preparation of the medicine for treating myocardial ischemia-reperfusion injury is found.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the application of the hederagenin derivative in preparing the medicine for resisting myocardial ischemia-reperfusion injury.
The purpose of the invention is realized by the following technical scheme:
a hederagenin derivative with effect of resisting myocardial ischemia reperfusion injury has the following structural formula:
the hederagenin derivative with the effect of resisting myocardial ischemia reperfusion injury is obtained by the following method:
1. extracting radix Dipsaci (Dipsacus asper Wall) with ethanol, extracting with ethanol, acid hydrolyzing, purifying, and separating to obtain hederagenin.
2. Dissolving hederagenin in DMF, reacting with 1, 2-dichloroethane under the catalysis of anhydrous potassium carbonate, and separating with silica gel column to obtain compound hederagenin- (2-chloro) ethyl ester.
3. Dissolving compound hederagenin- (2-chloro) ethyl ester in DMF, adding anhydrous potassium carbonate, potassium iodide and triethylamine as catalysts, reacting with piperazine hexahydrate, and separating with silica gel column to obtain compound hederagenin- (2-piperazine) ethyl ester.
Dissolving the compound hederagenin- (2-piperazine) ethyl ester in dry dichloromethane, adding picolinic acid, EDC & HCL and HOBT, reacting at room temperature, and separating by silica gel column to obtain the derivative (3 beta, 23-dihydroxy oleanane-12 ene-28 hydroxy acid-2- [4- (2-formyl pyridine) -piperazine ] -ethyl ester).
The experimental data of the derivative of the invention are as follows: ESI-MS: m/z 690.90[ M + H ]]+；1H-NMR(400MHz，DMSO)δ：8.68-8.63(1H，m)，7.97-7.92(1H，m)，7.62-7.60(1H，m)，7.51-7.48(1H，m)，5.22(1H，12-CH)，4.50-4.48(1H，3-OH)，4.22-4.19(1H，23-OH)，4.12-4.05(2H，1’-CH2)，3.65-3.62(2H，3-CH，23-CH2)，3.50-3.43(4H，4”-CH2，2”-CH2)，3.10-3.05(1H，23-CH)，2.80-2.74(1H，11-CH)，2.62-2.60(4H，1”-CH2，3”-CH2)，2.45-2.40(2H，2’-CH2)，2.02-1.92(1H，18-H)，1.85-1.17(20H)，1.10(3H，29-CH3)，1.05-1.02(1H)，0.85(6H，26-CH3，30-CH3)，0.83(3H，27-CH3)，0.65(3H，25-CH3)，0.54(3H，24-CH3)；13C-NMR(100MHz，DMSO)δ：176.2(C-28)，166.2(C-1”’)，153.9(C-3”’)，148.2(C-4”’)，143.1(C-13)，137.1(C-6”’)，124.4(C-2”’)，123.7(C-5”’)，121.1(C-12)，70.0(C-3)，64.8(C-23)，61.5(C-1’)，55.4(C-1”，C-3”)，52.8(C-2”，C-4”)，52.2(C-2’)，47.8(C-5)，46.2(C-9)，45.8(C-17)，45.2(C-19)，41.6(C-14)，41.3(C-4)，40.7(C-18)，38.2(C-8)，37.4(C-1)，36.3(C-10)，33.0(C-21)，32.3(C-29)，32.1(C-7)，31.8(C-22)，30.3(C-20)，27.5(C-15)，26.4(C-2)，25.5(C-27)，23.1(C-30)，22.8(C-11)，22.4(C-16)，17.8(C-06)，16.4(C-26)，15.3(C-25)，12.2(C-24)。
The hederagenin derivative with the effect of protecting myocardial ischemia-reperfusion injury can be applied to preparation of medicines for treating myocardial ischemia-reperfusion injury, and the prepared preparations comprise tablets, capsules, granules, oral liquid, pills, injections and other formulations.
The invention has the characteristics that: the chemical modification is carried out on hederagenin extracted from teasel roots as a lead compound to obtain the derivative, and pharmacological experiments prove that the derivative has the effect of resisting myocardial ischemia.
The invention has the beneficial effects that:
(1) the derivative can further improve the solubility of hederagenin, and has better advantages in the aspects of physicochemical property and pharmacy;
(2) the hederagenin derivative has a protective effect on myocardial ischemia reperfusion injury, and the activity of the hederagenin derivative is obviously superior to that of a parent compound, namely hederagenin.
(3) The hederagenin derivative obviously improves the cell survival rate of a myocardial cell ischemia reperfusion injury model.
(4) The hederagenin derivative can obviously reduce the LDH content in the supernatant of myocardial cells in a myocardial cell ischemia reperfusion injury model.
(5) The hederagenin derivative provided by the invention enables the MDA content in cells to be reduced and the ROS level to be obviously reduced.
The derivative of the invention has protective effect on hypoxia reoxygenation injury of myocardial ischemia reperfusion injury, and the pharmacological effects are proved by the following pharmacodynamic test examples.
1. Experimental methods
1.1H 9c2 cell culture
Taking H9c2 cardiomyocytes in DMEM high-glucose medium (hereinafter referred to as culture solution) containing 20% FBS and 1% double antibody at 37 ℃ and 5% CO2、95％O2Culturing in a cell culture box under the condition, and changing the culture solution once every 2 days. When the cell coverage rate is more than 80%, the cells are passaged, the culture medium is discarded, then 3mL of PBS is used for washing the cells, and then 2mL of PBS is added0.25% trypsin digestion, dynamic detection under microscope, when cells detached from the bottle wall, 5mL of medium was added to stop digestion. The cells were transferred into a centrifuge tube, centrifuged at 1000rpm for 5min, and placed in a petri dish for the experiment.
1.2 model construction
Taking cultured myocardial cells H9c2, discarding the original culture solution, and adding serum-free and sugar-free DMEM medium (previously used with 95% N)2+5％CO2Saturation), cells were placed in a cell bath with 95% N2+5％CO2Culturing in an anaerobic incubator for 2h, and carrying out oxygen deficiency. 2h later, the sugar-free medium was changed to the original medium, and the cells were incubated at 37 deg.C with 5% CO2、95％O2Culturing in an incubator for 4h, and reoxygenating.
1.3 grouping and administration
Cultured primary cells were randomly divided into normal groups: normally culturing; model group (H/R group): experimental groups: respectively preparing hederagenin (Hed) and its derivative series solutions to concentration of 20, 40, 80 μ M, pretreating cardiac muscle cells for 30min, and performing the same model group.
1.4 cell Activity assays
1.4.1 detection of H9c2 cell viability
Taking cultured H9c2 cardiomyocytes in a 96-well plate, placing the cardiomyocytes in the 96-well plate at 37 ℃ with the volume fraction of 5% CO2Culturing in incubator for 24 hr, adding 100 μ LMTT after molding administration, placing at 37 deg.C and 5% CO2、95％O2Culturing for 4h in an incubator; removing supernatant, adding 100 μ L DMSO, oscillating for 10min, and detecting light absorbance at 490nm with microplate reader after crystal is completely dissolved. Cell viability was ═ (experimental/normal) x 100%. The experiment was repeated 3 times.
1.4.2 detection of MDA content, ROS level in H9c2 cells and LDH content in supernatant
Following treatment according to the molding dosing, H9c2 cells and cell culture supernatants were collected separately and MDA content and ROS levels in the cells and LDH content in the culture supernatants were determined with reference to MDA, ROS, LDH detection kit instructions. The experiment was repeated 3 times.
1.4.3 statistical treatment
Data analysis was performed using SPSS 21.0. The comparison of the survival rate of cells among groups, the MDA content, the ROS level and the LDH content in culture supernatant adopts single-factor variance analysis, and the difference of P <0.05 has statistical significance.
2. Results
2.1 comparison of cell viability in H9c2
The survival rate of the hederagenin and the derivative thereof on H9c2 cells is detected by an MTT method, compared with an H/R group, the cell survival rate of the hederagenin (Hed) and the derivative thereof treatment group (20, 40 and 80 mu M) is increased and has dose dependence (P is less than 0.05), wherein the derivative has obvious activity, the amplitude of increasing the cell survival rate is 54.20 percent, the activity is stronger than that of the hederagenin (Hed), and the experimental result is shown in figure 1.
2.2 comparison of LDH content in H9c2 cells
Compared with the H/R group, the treatment groups (20, 40 and 80 mu M) of the hederagenin group (Hed) and the derivatives thereof reduce the LDH content in the supernatant of the myocardial cells (P is less than 0.05), the treatment groups (20, 40 and 80 mu M) of the hederagenin group (Hed) and the derivatives thereof have dose dependence, wherein the effect of the derivatives on reducing the LDH content in the supernatant of the myocardial cells is more obvious, the reduction of the LDH content in the supernatant of the myocardial cells is 65.1%, and the experimental result is shown in figure 2.
2.3 comparison of MDA content and ROS level in H9c2 cells
Compared with the H/R group, the hederagenin (Hed) and the derivative treatment group (20, 40 and 80 mu M) thereof reduce the MDA content and the ROS level in the cells obviously and have dose dependence (P is less than 0.05), the derivative reduces the MDA content in the cells by 55.9 percent and reduces the ROS level in the cells by 71.9 percent, compared with the hederagenin (Hed), the derivative has obvious effects of reducing the MDA content and the ROS level in the cells, and the experimental results are shown in figures 3 and 4.
Drawings
FIG. 1 is a graph comparing the viability of the derivatives and hederagenin on H9c2 cells.
FIG. 2 is a graph comparing the LDH content of H9c2 cell supernatant of derivatives and hederagenin
FIG. 3 is a graph comparing the MDA content in H9c2 cells of derivatives and hederagenin
FIG. 4 is a graph comparing the intracellular ROS levels of derivatives and hederagenin versus H9c2
Detailed Description
The following describes embodiments of the present invention in further detail with reference to examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of hederagenin
1kg of radix dipsaci is taken, 30g of calcium oxide is added, and 8 times of 60 percent ethanol is used for reflux extraction for 3 times, and each time lasts for 2 hours. Mixing the three extractive solutions, filtering, recovering ethanol from the filtrate until no alcohol smell exists, adding water to 3000ml, passing through treated macroporous resin column, eluting with 20% ethanol containing sodium hydroxide (pH 13) for 3 times of column volume, eluting with water to neutrality, eluting with 70% ethanol for 4 times of column volume, collecting eluate, and concentrating under reduced pressure to dry; hydrolyzing with 12 times of 40% ethanol solution containing 2N hydrochloric acid for 3 hr. Filtering, removing hydrolysate, washing filter cake with deionized water to neutrality; heating to boil with 95% ethanol, adding medicinal active carbon 2% of the medicinal liquid volume, filtering, concentrating the filtrate under reduced pressure, recovering, and drying to obtain radix Dipsaci total sapogenin. Dissolving radix Dipsaci total sapogenin with methanol, separating and purifying on C-18 reverse phase column (normal pressure or medium low pressure), eluting with 85% methanol-containing water solution, collecting hederagenin fractions, identifying with thin layer, mixing, and volatilizing part of solvent to obtain hederagenin crystal. The content was 98.6%.
EXAMPLE 2 preparation of hederagenin- (2-chloro) ethyl ester
Adding 2.116mmol of hederagenin into a round-bottom flask, dissolving with 30mL of DMF, adding 5mmol of anhydrous sodium carbonate, stirring at room temperature for 30min, adding 20mL of 1, 2-dichloroethane, reacting at 100 ℃ for 6h, detecting the reaction end point by TLC, recovering the solvent after the reaction is complete, dissolving with ethyl acetate, washing with water and saturated saline water for 3 times, each time 50mL, adding anhydrous sodium sulfate for dehydration, filtering, concentrating, and drying. Separating with silica gel chromatographic column (petroleum ether: ethyl acetate: 3: 2), collecting the same components, recovering solvent, and drying to obtain the final product
EXAMPLE 3 preparation of hederagenin- (2-piperazine) ethyl ester
Dissolving 1.000mmol of hederagenin- (2-chloro) ethyl ester in 20mL of DMF, adding 2.5mmol of anhydrous sodium carbonate, stirring for 30min, sequentially adding 0.05mmol of potassium iodide, 5mmol of piperazine hexahydrate and 5 drops of triethylamine, reacting at 100 ℃ for 6h, detecting the reaction end point by TLC (thin layer chromatography), pouring the reaction solution into water after the reaction is completed, stirring, carrying out suction filtration, washing a filter cake to be neutral, drying, separating by using a silica gel chromatographic column (trichloromethane: methanol: 5: 1), collecting the same components, recovering the solvent, and drying to obtain the hederagenin-ethyl ester.
Example 43 beta, 23-Dihydroxyolean-12-ene-28-carboxylic acid 2- [4- (2-Formylpyridine) -piperazinyl]-B
Preparation of esters
Weighing 1.000mmol of a compound 3 beta, 23-dihydroxy oleanane-12 ene-28 hydroxy acid-2- [4- (2-formylpyridine) -piperazinyl ] -ethyl ester, dissolving the compound with 50mL of dichloromethane, adding 1.5mmol of 2-picolinic acid, sequentially adding 1.5mmol of EDC & HCL and 1.5mmol of HOBT, reacting at room temperature for 6 hours, after the reaction is completed, adding dichloromethane to dilute the reaction solution, washing the dichloromethane solution with water and saturated saline solution for three times, 50mL each time, dehydrating with anhydrous sodium sulfate, filtering, drying, separating with a silica gel chromatographic column (chloroform: methanol ═ 30: 1), collecting the same components, recovering the solvent, and drying to obtain the compound.
Claims (3)
1. A hederagenin derivative is structurally characterized in that:
2. use of the hederagenin derivative according to claim 1 in the preparation of a medicament for resisting myocardial hypoxia reoxygenation injury.
3. Use of the hederagenin derivative according to claim 1 in the preparation of a medicament for treating myocardial ischemia-reperfusion injury.
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