Isoflavone-chalcone dimer and chalcone dimer, preparation method and application
阅读说明：本技术 异黄酮-查尔酮二聚体和查尔酮二聚体及制备方法和用途 (Isoflavone-chalcone dimer and chalcone dimer, preparation method and application ) 是由 杨学东 王立娜 于 2019-09-30 设计创作，主要内容包括：本发明公开了一种异黄酮-查尔酮二聚体和查尔酮二聚体及制备方法和用途,通过对藏药藏锦鸡儿进行提取分离和系统的化学成分研究和炎症介质抑制活性评价,本发明提供的四个新的黄酮二聚体类化合物具有抑制IL-6、TNF-α和NO生成的活性,可用于制备抗炎、治疗缺血性心脑血管疾病药物。(The invention discloses an isoflavone-chalcone dimer and a chalcone dimer, a preparation method and application thereof, wherein four novel flavone dimer compounds provided by the invention have the activity of inhibiting IL-6, TNF-alpha and NO generation by carrying out extraction and separation on Tibetan medicine caragana and systematic chemical component research and inflammation medium inhibition activity evaluation, and can be used for preparing medicaments for resisting inflammation and treating ischemic cardiovascular and cerebrovascular diseases.)
1. A compound represented by the following structure:
2. a process for the preparation of a compound according to claim 1, comprising the steps of:
(1) pulverizing radix Caraganae Sinicae, extracting with solvent, and recovering extractive solution to obtain total extract;
(2) dispersing the total extract obtained in the step (1) in water, extracting by adopting an organic solvent immiscible with water, and recovering the solvent to obtain an extract;
(3) separating the extract obtained in the step (2) by medium-pressure liquid chromatography, and performing gradient elution by using a methanol/water or acetonitrile/water mixed solvent as a mobile phase;
(4) and (4) separating the fractions obtained in the step (3) by preparative high performance liquid chromatography, and performing gradient elution by using methanol/water or acetonitrile/water as a mobile phase to obtain the compounds 1-4.
3. The method for producing a compound according to claim 2, wherein the Caragana ***a is a red wood heart of a rhizome of Caragana microphylla (Caragana jubata) of Caragana of Leguminosae (Leguminosae), Caragana changii (Caragana changduensis) and Caragana chuanensis (Caragana tiebetica).
4. The preparation method of the compound according to claim 2, wherein the extraction method in the step (1) is heating reflux extraction, leaching, percolation or ultrasonic extraction, the used solvent is at least one of dichloromethane, chloroform, ethyl acetate, methanol, ethanol, methanol-water with the concentration of more than 60% or ethanol-water, and the weight-volume ratio of the medicinal materials to the solvent is 1: 4-1: 15.
5. The method for preparing the compound according to claim 2, wherein the organic solvent used in the extraction method of step (2) is any one of dichloromethane, chloroform, diethyl ether and ethyl acetate, and the volume ratio of the aqueous solution to the organic solvent is 1: 1-1: 2.
6. The method for preparing the compound according to claim 2, wherein the elution is carried out in a gradient of 25: 75 to 100:0 in a methanol/water system or in a gradient of 20: 80 to 90: 10 in an acetonitrile/water system in the step (3).
7. The method for preparing the compound according to claim 2, wherein the methanol/water or acetonitrile/water in the step (4) is eluted at a gradient of 30: 70 to 90: 10 by volume ratio.
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
9. The use of the compound of claim 1 and the pharmaceutical composition of claim 8 in the preparation of anti-inflammatory and ischemic cardiovascular and cerebrovascular diseases drugs.
10. The use according to claim 9, wherein the anti-inflammatory agent is an agent that inhibits the activity of IL-6, TNF-a and NO production.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to isoflavone-chalcone dimers (caraganins A and B) and chalcone dimers (caraganins C and D) in Tibetan medicine caragana, and a preparation method and application thereof.
Background
Caragana ***a is taken as one of the main Tibetan medicines for blood breaking and stasis removal in Tibetan medicine, and is mainly prepared by using red wood hearts of three plants, namely Caragana phalloidea (Caragana jubata), Caragana changduensis (Caragana gigansis) and Caragana chuanensis (Caragana tibetaca) in Caragana of leguminosae and in Qinghai province of Qinghai-Tibet high-altitude origin. The caragana ***a has the main effects of breaking blood, dissolving stasis and reducing blood pressure, and is commonly used for treating diseases such as hyperemia, hypertension, irregular menstruation and the like.
Inflammation is a process by which human tissues produce a self-protective response when invading the body by foreign pathogens and harmful stimuli, involving the local vascular system and the immune system, as well as a variety of molecular mediators in the damaged tissue. However, uncontrolled inflammation may lead to a range of diseases. Ischemic cardiovascular and cerebrovascular diseases are one of the most serious diseases in humans, and can cause pathological changes in the body, which are caused by such uncontrolled inflammation. Therefore, controlling the cascade activation of inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor (TNF- α) and Nitric Oxide (NO) is a promising approach for the treatment of inflammatory diseases as well as ischemic cardiovascular and cerebrovascular diseases.
Disclosure of Invention
The invention provides an isoflavone-chalcone dimer and a chalcone dimer, a preparation method and application thereof, and solves the problem that few medicines for treating inflammatory diseases can be selected in the prior art.
The technical scheme of the invention is as follows:
a compound represented by the following structure:
the preparation method of the compound comprises the following steps:
(1) pulverizing radix Caraganae Sinicae, extracting with solvent, and recovering extractive solution to obtain total extract;
(2) dispersing the total extract obtained in the step (1) in water, extracting by adopting an organic solvent immiscible with water, and recovering the solvent to obtain an extract;
(3) separating the extract obtained in the step (2) by medium-pressure liquid chromatography, and performing gradient elution by using a methanol/water or acetonitrile/water mixed solvent as a mobile phase;
(4) and (4) separating the fractions obtained in the step (3) by preparative high performance liquid chromatography, and performing gradient elution by using methanol/water or acetonitrile/water as a mobile phase to obtain the compounds 1-4.
The Caragana ***a is red wood heart of rhizome of Caragana microphylla (Caragaajubata) of Caragana of Leguminosae (Leguminosae), Caragana changduensis (Caragana changduensis) and Caragana chuanensis (Caragana tibetaca).
The extraction method in the step (1) comprises heating reflux extraction, leaching, percolation or ultrasonic extraction, wherein a solvent is at least one of dichloromethane, chloroform, ethyl acetate, methanol, ethanol and methanol-water or ethanol-water with the concentration of more than 60%, and the weight-volume ratio of the medicinal materials to the solvent is 1: 4-1: 15.
In the extraction method in the step (2), the organic solvent is any one of dichloromethane, chloroform, diethyl ether and ethyl acetate, and the volume ratio of the aqueous solution to the organic solvent is 1: 1-1: 2.
In the step (3), gradient elution is carried out by a methanol/water system at a ratio of 25: 75-100: 0, or gradient elution is carried out by an acetonitrile/water system at a ratio of 20: 80-90: 10. Wherein the optimized ratio of the methanol/water system is 40: 60-95: 5, and the optimized ratio of the acetonitrile/water system is 35: 65-80: 20.
And (4) carrying out gradient elution on methanol/water or acetonitrile/water in a volume ratio of 30: 70-90: 10, wherein the optimized ratio is 50: 50-80: 10.
A pharmaceutical composition comprising a compound of
The compound and the pharmaceutical composition are applied to the preparation of anti-inflammatory and ischemic cardiovascular and cerebrovascular disease drugs.
The anti-inflammatory agent is an agent that inhibits the activity of IL-6, TNF-alpha and NO production.
The invention has the beneficial effects that: through systematic chemical component research and inflammation medium inhibition activity evaluation on Tibetan medicine caragana, the research discovers that the four novel flavone dimer compounds provided by the invention have the activity of inhibiting the generation of IL-6, TNF-alpha and NO, and can be used for preparing medicines for resisting inflammation and treating ischemic cardiovascular and cerebrovascular diseases.
Drawings
FIG. 1 HRESIMS spectra of
FIG. 2 Process for preparation of
FIG. 3 preparation of
FIG. 4 DEPT-135 spectrum of
FIG. 5 preparation of
FIG. 6 HSQC spectra of
FIG. 7 HMBC spectra of
FIG. 8 HRESIMS spectra of
FIG. 9 preparation of
FIG. 10 preparation of
FIG. 11 DEPT-135 spectrum of
FIG. 12 preparation of
FIG. 13 HSQC spectra of
FIG. 14 HMBC spectra of
FIG. 15 HRESIMS spectra of
FIG. 16 preparation of
FIG. 17 preparation of
FIG. 18 DEPT-135 spectrum of
FIG. 19 preparation of
FIG. 20 HSQC spectra of
FIG. 21 HMBC spectrum of
FIG. 22 NOESY spectrum of
FIG. 23 HRESIMS spectra of
FIG. 24 preparation of
FIG. 25 of
FIG. 26 DEPT-135 spectrum of
FIG. 27 of
FIG. 28 HSQC spectra of
FIG. 29 HMBC spectrum of
FIG. 30 NOESY spectrum of
FIG. 31 HMBC and1H-1h COSY correlation scheme;
FIG. 32 is a NOESY-related schematic of compounds 3-4 of the present invention;
FIG. 33 Experimental and calculated ECD spectra of compounds 1-4 of the present invention;
FIG. 34 structural formulas of the
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
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