CN108191945B - application of Japanese herba coptidis extract in preparation of α -glucosidase inhibitor drug - Google Patents
application of Japanese herba coptidis extract in preparation of α -glucosidase inhibitor drug Download PDFInfo
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Abstract
the invention provides an application of a Japanese herba coptidis extract in preparing α -glucosidase inhibitor drugs, wherein the Japanese herba coptidis extract is a compound with a formula as follows,
Description
Technical Field
the invention belongs to the field of application of a Chinese goldthread extract, and particularly relates to application of a Japanese goldthread extract in preparation of α -glucosidase inhibitor drug.
Background
the α -glucosidase inhibitor can delay the transformation and absorption of carbohydrate substances such as starch, cane sugar and the like in the digestive tract, reduce the burden of the kidney, control the rapid rise of blood sugar after meal and reduce the fluctuation of blood sugar concentration, so that the novel α -glucosidase inhibitor can be developed to effectively control the blood sugar.
Japanese buttercup root (Picris japonica Thunb.) is a plant of Compositae, also called "Swiss food". It has effects in clearing away heat, relieving swelling and pain. The common oral Japanese common goldthread decoction is taken to prevent diabetes; the prior art discloses that the water extract of the Japanese herba coptidis has obvious effect of reducing blood sugar, and discloses that the blood sugar reducing effect of extracts of other parts is obviously lower than that of the water extract of the Japanese herba coptidis; based on the above research, the blood sugar reducing effect of other parts of the Japanese herba coptidis remains to be further researched.
Disclosure of Invention
In order to solve the problems in the prior art, the invention discovers a novel compound with the hypoglycemic effect in the Japanese buttercup root extract and particularly discloses a preparation method of the compound.
The specific technical scheme of the invention is as follows:
the invention provides an application of a Japanese herba coptidis extract in preparing an alpha-glucosidase inhibitor drug, wherein the Japanese herba coptidis extract is a compound shown in the formula (I), and has the following structure:
in a further improvement, the Japanese herba coptidis extract is applied to the preparation of a medicament for preventing or treating diabetes caused by α -glucosidase.
In a further improvement, the compound of the formula is extracted from Japanese buttercup root.
In another aspect, the present invention provides a method for extracting an extract of japanese goldthread, comprising the steps of:
a: weighing herba coptidis japonicae, crushing, and carrying out ultrasonic treatment with petroleum ether for three times in an ultrasonic instrument, wherein the treatment conditions are as follows: the solid-liquid ratio of the Japanese herba coptidis and petroleum ether is 1:7, the ultrasonic power is 120-130W, the ultrasonic time is 5-6min, the ultrasonic temperature is 2-5 ℃, and filtering is carried out to obtain filter residue;
b: extracting the residue with 95% ethanol solution under reflux for three times, adding 12.5 times of ethanol solution for the first time, refluxing for 2.5 hr, adding 8 times of ethanol solution for the second time, refluxing for 2 hr, adding 6.5 times of ethanol solution for the third time, refluxing for 2 hr, mixing filtrates, filtering, and recovering ethanol to obtain ethanol extract;
c: eluting the ethanol extract by column chromatography, and recrystallizing to obtain herba Lagotis Japonicae extract.
The further improvement, the specific method of step C column chromatography is as follows:
c-1: dissolving the ethanol extract with ethanol, loading on silica gel column, eluting with eluent, eluting with cyclohexane, and discarding the eluent; eluting with a mixed solution of cyclohexane and ethyl acetate at a volume ratio of 17:1, and discarding the eluent; eluting with a mixed solution of cyclohexane and ethyl acetate at a volume ratio of 10:1, and discarding the eluent; eluting with a mixture of cyclohexane and ethyl acetate at a ratio of 8.5:1, and collecting the eluate; concentrating to obtain crude extract.
10-20 column volumes can be eluted as required in the elution process by cyclohexane, and 20-30 column volumes can be eluted as required when 17:1 cyclohexane and ethyl acetate mixed solution is eluted; when the mixture of cyclohexane and ethyl acetate in the ratio of 10:1 is eluted, TLC is used for monitoring the appearance of the target substances, when the target substances exist, the eluent is discarded, the mixture of cyclohexane and ethyl acetate in the volume ratio of 8.5:1 is directly used for elution, and the eluent is collected and concentrated.
Further improvement, the specific recrystallization method in the step C comprises the following steps:
c-2: recrystallizing the crude extract by using a recrystallization solvent, wherein the recrystallization solvent is a mixture of 1: 3:12 of a mixture of acetone, dichloromethane and petroleum ether.
In a further improvement, the solid-to-liquid ratio of the crude extract to the recrystallization solvent is 1: 16.
Further improvement, the specific conditions of recrystallization are as follows: placing the crude extract in a mixed solution of acetone and dichloromethane, heating to 50 deg.C, maintaining the temperature, dropwise adding petroleum ether, slowly cooling to room temperature, standing, filtering, and collecting precipitate.
The recrystallized material also needs to be separated by preparative chromatography on reverse phase HPLC (C18, 250 mm. times.10 mm, 5 μm) if necessary.
the invention provides a novel compound which can inhibit alpha-glucosidase and is found in a Japanese herba coptidis extractive, and the compound can be used for preparing α -glucosidase inhibitor drug, so that the effect of preventing or treating diabetes caused by alpha-glucosidase is better than that of a Japanese herba coptidis aqueous extractive and an alcohol extractive, and is equivalent to that of a commercially available hypoglycemic drug.
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1A method for extracting an extract of Coptis japonica
The extraction method comprises the following steps:
a: weighing herba coptidis japonicae, crushing, and carrying out ultrasonic treatment with petroleum ether for three times in an ultrasonic instrument, wherein the treatment conditions are as follows: the solid-liquid ratio of the Japanese herba coptidis and petroleum ether is 1:7, the ultrasonic power is 120W, the ultrasonic time is 5min, the ultrasonic temperature is 2 ℃, and filtering is carried out to obtain filter residue;
b: extracting the residue with 95% ethanol solution under reflux for three times, adding 12.5 times of ethanol solution for the first time, refluxing for 2.5 hr, adding 8 times of ethanol solution for the second time, refluxing for 2 hr, adding 6.5 times of ethanol solution for the third time, refluxing for 2 hr, mixing filtrates, filtering, and recovering ethanol to obtain ethanol extract;
c: eluting the ethanol extract by column chromatography, and recrystallizing to obtain herba Lagotis Japonicae extract. Example 2A method for extracting an extract of Coptis japonica
The extraction method comprises the following steps:
a: weighing herba coptidis japonicae, crushing, and carrying out ultrasonic treatment with petroleum ether for three times in an ultrasonic instrument, wherein the treatment conditions are as follows: the solid-liquid ratio of the Japanese herba coptidis and petroleum ether is 1:7, the ultrasonic power is 130W, the ultrasonic time is 6min, the ultrasonic temperature is 5 ℃, and filtering is carried out to obtain filter residue;
b: extracting the residue with 95% ethanol solution under reflux for three times, adding 12.5 times of ethanol solution for the first time, refluxing for 2.5 hr, adding 8 times of ethanol solution for the second time, refluxing for 2 hr, adding 6.5 times of ethanol solution for the third time, refluxing for 2 hr, mixing filtrates, filtering, and recovering ethanol to obtain ethanol extract;
c: eluting the ethanol extract by column chromatography, and recrystallizing to obtain herba Lagotis Japonicae extract.
Example 3A method for extracting an extract of Coptis japonica
The extraction method comprises the following steps:
a: weighing herba coptidis japonicae, crushing, and carrying out ultrasonic treatment with petroleum ether for three times in an ultrasonic instrument, wherein the treatment conditions are as follows: the solid-liquid ratio of the Japanese herba coptidis and the petroleum ether is 1:7, the ultrasonic power is 125W, the ultrasonic time is 5.5min, the ultrasonic temperature is 2-5 ℃, and filtering is carried out to obtain filter residue;
b: extracting the residue with 95% ethanol solution under reflux for three times, adding 12.5 times of ethanol solution for the first time, refluxing for 2.5 hr, adding 8 times of ethanol solution for the second time, refluxing for 2 hr, adding 6.5 times of ethanol solution for the third time, refluxing for 2 hr, mixing filtrates, filtering, and recovering ethanol to obtain ethanol extract;
c: eluting the ethanol extract by column chromatography, and recrystallizing to obtain the Japanese common goldenrod herb extract, wherein the specific method comprises the following steps:
c-1: dissolving the ethanol extract with ethanol, loading on silica gel column, eluting with eluent, eluting with cyclohexane, and discarding the eluent; eluting with a mixed solution of cyclohexane and ethyl acetate at a volume ratio of 17:1, and discarding the eluent; eluting with a mixed solution of cyclohexane and ethyl acetate at a volume ratio of 10:1, and discarding the eluent; eluting with a mixture of cyclohexane and ethyl acetate at a ratio of 8.5:1, and collecting the eluate; concentrating to obtain crude extract;
c-2: recrystallizing the crude extract by using a recrystallization solvent, wherein the recrystallization solvent is a mixture of 1: 3:12 of a mixture of acetone, dichloromethane and petroleum ether.
Example 4A method for extracting an extract of Coptis japonica
The extraction method comprises the following steps:
a: weighing herba coptidis japonicae, crushing, and carrying out ultrasonic treatment with petroleum ether for three times in an ultrasonic instrument, wherein the treatment conditions are as follows: the solid-liquid ratio of the Japanese herba coptidis and the petroleum ether is 1:7, the ultrasonic power is 125W, the ultrasonic time is 5.5min, the ultrasonic temperature is 2-5 ℃, and filtering is carried out to obtain filter residue;
b: extracting the residue with 95% ethanol solution under reflux for three times, adding 12.5 times of ethanol solution for the first time, refluxing for 2.5 hr, adding 8 times of ethanol solution for the second time, refluxing for 2 hr, adding 6.5 times of ethanol solution for the third time, refluxing for 2 hr, mixing filtrates, filtering, and recovering ethanol to obtain ethanol extract;
c: eluting the ethanol extract by column chromatography, and recrystallizing to obtain the Japanese common goldenrod herb extract, wherein the specific method comprises the following steps:
c-1: dissolving the ethanol extract with ethanol, loading on silica gel column, eluting with eluent, eluting with cyclohexane, and discarding the eluent; eluting with a mixed solution of cyclohexane and ethyl acetate at a volume ratio of 17:1, and discarding the eluent; eluting with a mixed solution of cyclohexane and ethyl acetate at a volume ratio of 10:1, and discarding the eluent; eluting with a mixture of cyclohexane and ethyl acetate at a ratio of 8.5:1, and collecting the eluate; concentrating to obtain crude extract;
c-2: and (3) recrystallizing the crude extract by using a recrystallization solvent, wherein the solid-liquid ratio of the crude extract to the recrystallization solvent is 1:16, and the volume ratio of the recrystallization solvent is 1: 3:12 of a mixed solution of acetone, dichloromethane and petroleum ether, wherein the specific conditions are as follows: placing the crude extract in mixed solution of acetone and dichloromethane, heating to 50 deg.C, maintaining the temperature, adding petroleum ether dropwise, slowly cooling to room temperature, standing, filtering, collecting precipitate, drying, and separating by reversed phase HPLC semi-preparative chromatography to obtain white powder.1H-NMR(400MHz，CDCl3)δ:5.23(1H，dd，J＝3.7，3.7，H-12)，
4.10(1H，m，H-2)，3.55(1H，m，H-22)，3.23(1H，d，J＝4.0，H-3)，1.99(1H，m，H-18)，1.26(3H，s，H-25)，1.15(3H，s，H-27)，1.03(3H，s，H-23)，1.02(3H，s，H-24)，1.00(3H，s，H-26)，0.99(3H，s，H-28)，0.93(3H，s，H-30)，0.92(3H，s，H-29)，0.84(1H，m，
H-5)；13C-NMR(100MHz，CDCl3)δ:143.9(C-13)，122.6(C-12)，78.6(C-3)，76.5(C-22)，71.3(C-2)，55.3(C-5)，48.2(C-9)，47.5(C-18)，46.2(C-19)，44.4(C-1)，42.9(C-21)，42.5(C-14)，40.2(C-8)，38.4(C-17)，38.3(C-4)，36.8(C-10)，33.5(C-29)，32.7(C-7)，31.8(C-20)，29.9(C-23)，26.5(C-27)，25.6(C-15)，25.1(C-30)，24.8(C-28)，23.8(C-11)，19.2(C-16)，18.3(C-6)，17.5(C-24)，16.9(C-26)，16.7(C-25)。
Experimental example 1 assay of inhibitory Activity of Coptis japonica extract on α -glucosidase
1.1 instruments and reagents
The instrument comprises the following steps: an enzyme-labeling instrument: ELISA plate reader (Bio-Tek Instruments, USA);
the reagents are α -Glucosidase (α -D-Glucosidase, Sigma, SOOU/ml), 4-nitrophenol- α -D-glucopyranoside (PNPC, Merck), reduced glutathione (Shanghai's product), acarbose, i.e. Babesylate (Bayer medicine and health care Co., Ltd., Beijing),
herba Ecliptae Japonici water extract (weighing herba Ecliptae Japonici 100g, soaking in 20 times of distilled water for 15min, decocting for 1h, filtering to obtain filtrate, adding 10 times of distilled water to the residue, decocting for 1h, filtering to obtain filtrate, mixing filtrates, centrifuging, and concentrating to obtain herba Ecliptae Japonici water extract)
The Japanese herba Lagotis alcohol extract is prepared by weighing 100g of Japanese herba Lagotis, soaking in 20 times of 95% ethanol for 15min, reflux extracting for 1h, filtering to obtain filtrate, reflux extracting the residue with 10 times of 95% ethanol for 1h, filtering, mixing filtrates, centrifuging, and concentrating.
1.2 test methods
the inhibition of the compound against α -glucosidase was measured colorimetrically, phosphate buffer (67 mmol/l, pH 6.8, 170. mu.l), reduced glutathione (mg/ml, 5. mu.l), α -glucosidase (diluted with phosphate buffer to 0.2U/ml, 25. mu.l), acarbose, compound of formula (I), aqueous extract of Japanese stephania, and alcohol extract of Japanese stephania were dissolved in dimethyl sulfoxide, diluted with phosphate buffer to 25. mu.l per well to a final concentration of 0.5 mg/ml, 2 mg/ml, and finally, substrate 4-nitrophenol- α -D-glucopyranoside (23.2 mmol/l, 25. mu.l) was added thereto at 37 ℃ after 15 minutes of water bath reaction, sodium carbonate (1 mol/l, 50. mu.l) was added thereto, colorimetric-HCl buffer was used in place of the same volume of solvent in wells as in the control of the substrate of formula (OD) and the OD of each sample was calculated from the control values in Table 1.
table 1 results of inhibition of α -glucosidase activity by each group
1.3 conclusion of the experiment
the compound of the formula provided by the invention has the function of strongly inhibiting α -glucosidase, and the inhibiting activity of the compound exceeds that of acarbose and the aqueous extract and the alcohol extract of the Japanese herba coptidis.
Experimental example 2 hypoglycemic Effect of Coptis japonica extract on diabetic mice
2.1 materials of the experiment
2.1.1 Experimental animals
Kunming mouse, 20-22g in weight, half male and half female, provided by Experimental animals center of Shanxi medical university.
2.1.2 reagents and apparatus
A compound of formula (I) is prepared by the process provided by the present invention;
alloxan, physiological saline, glucose kit, glibenclamide were all purchased from pharmaceutical companies; the rest of the reagents are analytically pure; rotary evaporator, circulating water type vacuum pump, electric heating constant temperature water bath, ultraviolet visible spectrophotometer, temperature control electric heating jacket and centrifuge are also commercially available.
2.1 Experimental methods
2.1.1 establishment of Tetraoxypyrimidine diabetogenic mouse model
After a mouse is fasted for 12 hours without water prohibition, injecting the currently prepared physiological alloxan saline into the tail vein, after 72 hours, sampling blood for the retroorbital venous plexus of the mouse fasted for 12 hours, centrifuging at 3500r/min for L5 minutes, taking 10 mu L of serum, measuring the blood sugar value according to a glucose oxidase method of a glucose kit, and selecting a patient with fasting blood sugar higher than 11.1mmol/L for experiment.
2.1.2 Experimental groups and administrations
Randomly divided into 7 groups by blood glucose value, 10 per group: glibenclamide positive control group (2 mg/kg); an aqueous extract (2g/kg) of the Japanese copperleaf herb, an alcohol extract (2g/kg) of the Japanese copperleaf herb, a low dose (2mg/kg) of a compound of the formula (I), a medium dose group (6mg/kg) of the compound of the formula (I), a high dose group (10mg/kg) of the compound of the formula (I), a diabetes model group; another 10 normal mice were used as normal control groups. The diabetes model group and the normal control group are administered with physiological saline with equal volume, and the experimental mice are administered with the normal control group by intragastric administration, 0.2ml/10g, 1 time per day and 14 days of continuous administration.
2.1.3 blood sample Collection and measurement
The mice are fasted for 8 hours before administration on the 7 th day and the 14 th day, after continuous fasted for 2 hours after administration, blood is collected from the retroorbital venous plexus of the mice, centrifuged for L5min at 3500r/min, 10 mu L of serum is taken, and the fasting blood glucose value is measured according to the glucose oxidase method of the glucose kit.
2.1.4 data statistics and processing method
Mean ± difference of label for experimental data
Indicating the significance of the differences between the groups compared using the t-test.
2.1.5 results of the experiment
The results of the blood glucose effect of each group on diabetic mice are shown in table 2.
Table 2 results of the effect of groups on blood glucose in alloxan diabetic mice (n ═ 10)
Comparison with diabetes model group, P*＞0.05，P&Less than 0.05, P, in comparison with an aqueous extract of Ceratodon japonicus#Greater than 0.05, P, in comparison with the alcohol extract of Picris japonica#＜0.05。
2.1.6 conclusions of the experiment
As can be seen from the table above, the compound of the formula provided by the invention has very good blood sugar reducing effect, the effect is better than that of the Japanese herba coptidis alcohol extract, the effect is slightly better than that of the Japanese herba coptidis water extract, the curative effect is equivalent to that of the commercially available glibenclamide, and the compound of the formula is dose-dependent.
Claims (1)
1. The application of the Japanese herba coptidis extract in preparing the medicine for preventing or treating diabetes mellitus is disclosed, wherein the Japanese herba coptidis extract is a compound shown in the formula (I), and the structure is as follows:
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102085226A (en) * | 2011-01-21 | 2011-06-08 | 山西医科大学 | Japanese picris japonica extract and extracting method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102085226A (en) * | 2011-01-21 | 2011-06-08 | 山西医科大学 | Japanese picris japonica extract and extracting method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Composite constituents: three new triterpene triols isolated from fresh roots of Picris hieracioides subsp. Japonica;Shiojima, Kenji等;《Chemical & Pharmaceutical Bulletin》;19951231;第43卷(第10期);第1640页 * |
| 日本毛连菜降血糖物质基础研究;席啸虎;《山西医科大学硕士学位论文》;20111129;全文 * |
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