CN115215919A - Preparation of Kokoonol and application thereof in preparing medicament for treating diabetes - Google Patents
Preparation of Kokoonol and application thereof in preparing medicament for treating diabetes Download PDFInfo
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 39
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims description 15
- IKOBLAPERMAFGU-UHFFFAOYSA-N 28-hydroxy-D:A-friedooleanan-3-one Natural products CC12CCC3(CO)C4CC(C)(C)CCC4(C)CCC3(C)C2CCC2(C)C1CCC(=O)C2C IKOBLAPERMAFGU-UHFFFAOYSA-N 0.000 title description 5
- PAEAMKFTKUVQAG-UHFFFAOYSA-N Kokoonol Natural products CC1C(=O)CCC2C1(C)CCC3C2(C)CCC4(C)C5CC(C)(C)CCC5(C)CCC34CO PAEAMKFTKUVQAG-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention relates to the technical field of alpha-glucosidase inhibitors. The invention provides a new application of friedelane type triterpene koonol (the chemical structure of which is shown in a formula I), and particularly relates to an application of koonol in preparing a medicine for treating diabetes. The invention tests the inhibitory activity of koonol on alpha-glucosidase by using a compound extracted and separated from the traditional Chinese medicine Wen radix Codonopsis pilosulae (Codonopsis pilosula var. Modesta), and test results show that koonol has obvious inhibitory activity on alpha-glucosidase and IC 50 The value is 5.5 +/-0.5 mu M, which indicates that the compound has potential activity for treating diabetes, can be used for preparing a medicament for treating diabetes and can also be used for preparing a medicament for preventing and treating diabetes in an auxiliary way.
Description
1. Field of the invention
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to preparation and application of friedelane type triterpene kokoonol.
2. Background of the invention
Diabetes Mellitus (DM) is a condition in which insulin secretion is absolutely or relatively inadequate, resulting in poor insulin action; or sugar metabolism disorder caused by deficiency of both absolute and relative insulin secretion, and chronic metabolic diseases caused by fat, protein, water and electrolyte metabolism disorder. In recent years, the incidence of diabetes has increased year by year due to the improvement of living standard and the change of dietary structure, and the number of diabetic patients has also increased considerably. The latest data published in the 9 th edition of the International Diabetes Federation IDF (International Diabetes Federation) global Diabetes overview shows that 4.63 million adults have Diabetes in 2019, and by 2030, the number of global diabetic patients will reach 5.78 million people and by 2045 will jump to 7 million, so that the treatment of Diabetes has become a major public health problem worldwide.
Diabetes can be classified into Insulin Dependent Diabetes Mellitus (IDDM), non-Insulin Dependent Diabetes Mellitus (NIDDM), gestational Diabetes, and other specific types of Diabetes. Type I diabetes is associated with absolute insulin secretion deficiency, type II diabetes is mainly associated with insulin resistance, which may be accompanied by insulin hyposecretion to varying degrees, and type II diabetes accounts for more than 95% of the number of diabetes, most of gestational diabetes occurs in the middle and late stages of pregnancy, and is commonly seen in obese and elderly parturients. In addition, the onset of diabetes is often accompanied by many complications such as stroke, obesity, cancer, and cardiovascular disease. It has been reported that postprandial blood glucose status is an important factor in diagnosing the development of diabetes, while type II diabetes and increased risk of development of metabolic syndrome are associated with high concentrations of glucose in the plasma after meal. Therefore, controlling postprandial hyperglycemia is an effective method for treating diabetes and alleviating complications. Among the most effective methods for inhibiting postprandial hyperglycemia is to reduce the production of glucose by inhibiting the activity of α -glucosidase.
Alpha-glucosidase is a glycoside hydrolase that catalyzes the cleavage of alpha-glycosidic bonds between aryl or hydrocarbyl groups and sugar groups, thereby hydrolyzing disaccharides, polysaccharides to glucose. Alpha-glucosidase is widely found in animals, plants and microorganisms, is generally secreted by small intestinal mucosal epithelial cells in the animal body, and is attached to microvilli. By inhibiting the activity of alpha-glucosidase, the absorption of carbohydrates in the small intestine can be delayed, thereby reducing postprandial blood glucose and insulin levels. At present, α -glucosidase inhibitors have been recognized as effective type-ii diabetes (T2D) therapeutics. Among the α -glucosidase inhibitors currently being developed and marketed are: acarbose, voglibose, miglitol, etc. The alpha-glucosidase inhibitor mainly comes from three aspects of natural plants, microbial metabolites and chemical synthesis.
Wen radix Codonopsis (Codonopsis pilosula (Fr.) Pilosula (L.) Pilosula var. Modesta) is a plant of Codonopsis genus of Campanulaceae family (Campanulaceae), and is one of radix Codonopsis base source plants specified in 2020 edition pharmacopoeia of the people's republic of China. It has sweet taste and neutral nature, and has effects of invigorating spleen and replenishing qi, invigorating spleen and replenishing lung, nourishing blood and promoting fluid production, and can be used for treating spleen and lung qi deficiency, anorexia and listlessness, cough and asthma, qi and blood deficiency, sallow complexion, cardiopalmus and short breath, body fluid consumption thirst, internal heat and diabetes. In recent years, researches show that the codonopsis pilosula also has the hypoglycemic activity and can be used for treating diabetes.
3. Summary of the invention
The invention aims to provide a friedelane triterpenoid with medicinal value, and a preparation method and application thereof in preparation of medicines for preventing, treating and assisting in treating diabetes.
The compound and the pharmaceutically acceptable carrier thereof in the preparation of the medicament dosage form of the medicament for treating the diabetes mellitus comprise: tablets, capsules, granules, injections, gels, sustained-release formulations, targeted formulations, and the like, as will be appreciated by those skilled in the art.
The compound and the pharmaceutically acceptable carrier thereof are used for preparing the pharmaceutical dosage form of the medicament for preventing and treating the diabetes mellitus in an auxiliary way, and the pharmaceutical dosage form comprises the following components: tablets, capsules, granules, injections, gels, sustained-release formulations, targeted formulations, and the like, as will be appreciated by those skilled in the art.
The structure of the compound of the invention is shown as the formula (I):
the preparation method of the compound specifically comprises the following steps:
step (1): pulverizing dried root of Wen radix Codonopsis (Codonopsis pilosula var. Modesta) of Taoise province, soaking in 95% ethanol for one week, filtering with gauze to extract filtrate, soaking and extracting for three times, mixing filtrates, and concentrating under reduced pressure to obtain ethanol extract. Dissolving the ethanol extract in distilled water, and extracting with ethyl acetate, wherein the volume ratio of the ethyl acetate to the distilled water is 1;
step (2): subjecting the ethyl acetate extract to gradient elution using a silica gel (100-200 mesh) chromatography column, wherein the elution system is petroleum ether-acetone (V/V) 40;
and (3): combining Fr.3 parts by thin layer chromatography to obtain 2 parts, and collecting part 1 to obtain Fr.3.1 part; the fr.3.1 fractions were separated using silica gel (200-300 mesh) chromatography columns, and eluted in a gradient with petroleum ether-acetone (V/V) 40; section fr.3.1.2 is separated using a silica gel (200-300 mesh) chromatography column, eluting with a gradient of petroleum ether-acetone (V/V) 40.
The invention separates koonol from Wen radix codonopsitis and carries out the research on the inhibition activity of alpha-glucosidase on the koonol. The research result shows that: IC of kokonol on alpha-glucosidase inhibitory activity 50 The value is 5.5 +/-0.5 mu M, so the kokoonol has the potential of developing an alpha-glucosidase inhibitor, can be used for preparing a medicament for treating diabetes and can also be used for preparing a medicament for preventing and treating the diabetes in an auxiliary way.
4. Description of the drawings
FIG. 1 shows the structural formula of a compound kokonol.
FIG. 2 is a graph showing the results of the α -glucosidase inhibitory activity assay of the compounds of the present invention.
5. Detailed description of the preferred embodiments
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the present invention, and not all of the present invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention. The experimental procedures in the following examples are all conventional ones unless otherwise specified. The experimental materials used in the following examples are all commercially available unless otherwise specified.
Example 1: preparation method of compound of the invention
Wen Dang Shen used in the experiment was collected from Shang city of Longnan province in Gansu province.
Step (1): pulverizing dried root of Wen radix Codonopsis, soaking in 95% ethanol for one week, filtering with gauze, extracting the filtrate, soaking and extracting for three times, mixing filtrates, and concentrating under reduced pressure to obtain ethanol extract. Dissolving the ethanol extract in distilled water, and extracting with ethyl acetate, wherein the volume ratio of the ethyl acetate to the distilled water is 1;
step (2): gradient elution is performed on the ethyl acetate extract using a silica gel (100-200 mesh) chromatography column, with the elution system being petroleum ether-acetone (V/V) 40;
and (3): combining Fr.3 parts by thin layer chromatography to obtain 2 parts, and collecting part 1 to obtain Fr.3.1 part; the fr.3.1 fractions were separated using silica gel (200-300 mesh) chromatography columns, and eluted in a gradient with petroleum ether-acetone (V/V) 40; section fr.3.1.2 is separated using a silica gel (200-300 mesh) chromatography column, eluting with a gradient of petroleum ether-acetone (V/V) 40.
EXAMPLE 2 alpha-glucosidase inhibitory Activity test of kokoonol Compound of example 1
1. Principle of experiment
4-nitrophenol-alpha-D-glucopyranoside (PNPG) reacts with alpha-glucosidase to generate PNG. PNG is yellow and has ultraviolet absorption capacity, and the alpha-glucosidase inhibitor can inhibit the activity of alpha-glucosidase, so that the activity of the alpha-glucosidase is reduced, and the amount of generated PNG is reduced. The alpha-glucosidase inhibitory activity of the component to be measured was determined by measuring the absorbance value (A) obtained at 405nm using a plate reader. And (3) determining the activity of the target compound on the alpha-glucosidase inhibition by taking PNPG as a substrate.
2. Solution preparation
(1) PBS solution: naH (sodium hydroxide) 2 PO 4 +Na 2 HPO 4 Preparing a buffer solution with the pH value of 0.1M = 6.8;
(2)Na 2 CO 3 solution: 0.2M Na 2 CO 3 A solution;
(3) Substrate PNPG: weighing 4.5mg of PNPG, and dissolving in 1ml of PBS buffer solution with the concentration of 15mM;
(4) Alpha-glucosidase solution (0.4U/ml): weighing 0.4U alpha-glucosidase, and dissolving in 1ml PBS solution to obtain 0.4U/ml enzyme solution;
(5) Preparation of the target compound: weighing a target compound with the concentration of 200 mu M, and dissolving the target compound in 1ml of DMSO for preliminary screening; if the inhibition rate is more than 50%, performing a concentration gradient experiment.
3. Activity screening assay
The experiment was performed in 96-well plates with Acarbose (Acarbose) as a positive control drug. The experiment comprises four groups of blank control wells Ab, blank reaction wells At0, drug control wells Abi and drug reaction wells Ati. Wherein 112. Mu.L of PBS solution was added to each group, then 20. Mu.L of PBS solution was added to the control well group, and 20. Mu.L of enzyme solution was added to the reaction well group; the blank group was added with 8. Mu.L of DMSO solution, and the drug group was added with 8. Mu.L of DMSO solution of the sample to be tested. The well plate to which the above solution was added was incubated in an incubator at 37 ℃ for 15 minutes. After incubation, each reaction well of each group20 μ L of PNPG solution was added separately and incubated in an incubator at 37 ℃ for 30 minutes. After incubation, 80. Mu.L of Na was added to each reaction well of each group 2 CO 3 The solution was allowed to stop. The absorbance value (A) at 405nm was measured by placing the 96-well plate in a microplate reader, and the inhibition rate was calculated. The calculation formula of the inhibition rate is as follows: inhibition Rate = [1- (Ati-Abi)/(At 0-Ab)]×100％
The experiment is repeated for 4 times, and is divided into four groups of parallel experiments A, B, C and D.
The samples should be prescreened first, and after prescreening is completed, concentration gradient experiments are performed, graphPad simulation curves are used, and SPSS is used to calculate IC 50 The value is obtained.
4. Results of the experiment
TABLE 1 calculation of IC 50 Value of
By combining the analysis, the kokonol has better inhibitory activity to alpha-glucosidase, can be used for preparing the medicine for treating diabetes and can also be used for preparing the medicine for preventing and treating diabetes in an auxiliary way.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments or portions thereof without departing from the spirit and scope of the invention.
Claims (9)
1. The friedelane triterpenoid compound (hereinafter referred to as target compound) is named kokonol, and the structure of the friedelane triterpenoid compound is shown as the formula (I):
2. a process for the preparation of a compound according to claim 1: the method is characterized by comprising the following steps:
(1) Pulverizing dried root of Wen radix Codonopsis (Codonopsis pilosula Coodonopsis pilosula var. Modesta) of Taoise province, soaking in ethanol for one week, filtering with gauze to obtain filtrate, repeatedly soaking and extracting for three times, mixing filtrates, and concentrating under reduced pressure to obtain ethanol extract;
(2) Dissolving the ethanol extract obtained in the step (1) in distilled water, and extracting with ethyl acetate, wherein the volume ratio of ethyl acetate to distilled water is 1;
(3) Subjecting the ethyl acetate extract obtained in step (2) to gradient elution by using a silica gel (100-200 mesh) chromatographic column, wherein the elution system is petroleum ether-acetone (V/V) 40;
(4) Combining Fr.3 parts by thin layer chromatography to obtain 2 parts, and collecting part 1 to obtain Fr.3.1 part;
(5) Section fr.3.1 is separated using a silica gel (200-300 mesh) chromatography column, gradient elution with petroleum ether-acetone (V/V) 40;
(6) Section fr.3.1.2 was chromatographed using silica gel (200-300 mesh) eluting with a gradient of petroleum ether-acetone (V/V) 40.
3. A process for the preparation of a compound according to claim 2: characterized in that the ethanol concentration used in the step (1) is 95%.
4. The use of a compound according to claim 1 and a pharmaceutically acceptable carrier therefor in the manufacture of a medicament for the treatment of diabetes.
5. The use of a compound according to claim 4 and a pharmaceutically acceptable carrier thereof for the manufacture of a medicament for the treatment of diabetes, wherein said medicament for the treatment of diabetes is a medicament for inhibiting α -glucosidase activity.
6. The use of a compound of claim 4 and a pharmaceutically acceptable carrier therefor in the manufacture of a medicament for the treatment of diabetes, wherein said medicament comprises: tablet, capsule, granule, injection, gel, sustained-release preparation, targeting preparation, etc.
7. The use of a compound according to claim 1 and a pharmaceutically acceptable carrier thereof for the manufacture of a medicament for the prophylaxis and adjunctive treatment of diabetes.
8. The use of the compound according to claim 7 and a pharmaceutically acceptable carrier thereof for the preparation of a medicament for the prophylactic and adjunctive treatment of diabetes, wherein the medicament for the treatment of diabetes is a medicament for inhibiting α -glucosidase activity.
9. The use of a compound of claim 7 and a pharmaceutically acceptable carrier thereof for the manufacture of a medicament for the prophylactic and adjunctive treatment of diabetes, wherein the pharmaceutical dosage form comprises: tablet, capsule, granule, injection, gel, sustained-release preparation, targeting preparation, etc.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181446A (en) * | 2007-11-23 | 2008-05-21 | 广东工业大学 | Application of sitsang scindapsus aureus flower as well as extract thereof in the preparation of diabetes medicament |
| CN107141330A (en) * | 2017-04-01 | 2017-09-08 | 赵静 | One group of α glucosidase inhibitor and its application |
| CN108619321A (en) * | 2018-06-21 | 2018-10-09 | 大连大学 | Application of the Camellia nitidissima seed extract in alpha-glucosidase restrainer |
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2021
- 2021-04-19 CN CN202110421148.2A patent/CN115215919A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101181446A (en) * | 2007-11-23 | 2008-05-21 | 广东工业大学 | Application of sitsang scindapsus aureus flower as well as extract thereof in the preparation of diabetes medicament |
| CN107141330A (en) * | 2017-04-01 | 2017-09-08 | 赵静 | One group of α glucosidase inhibitor and its application |
| CN108619321A (en) * | 2018-06-21 | 2018-10-09 | 大连大学 | Application of the Camellia nitidissima seed extract in alpha-glucosidase restrainer |
Non-Patent Citations (2)
| Title |
|---|
| A.A.LESDIE GUNATILAKA等: "Studies on terpenoids and stereoids. Part 27. Structure of a D:A-friedo-oleanane triterpenoid from salacia reticulata and revision of the structures of kokoonol and kokzeylanol series of triterpenoids" * |
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