阅读说明：本技术 一组倍半萜类化合物及其制备方法和应用 (Sesquiterpenoids and preparation method and application thereof ) 是由 何祥久 王宜海 孙莲莲 徐静雯 于 2019-09-27 设计创作，主要内容包括：本发明属于医药技术领域,提供了一组倍半萜化合物及其制备方法和应用,通过理化常数和现代波谱学对从三裂蟛蜞菊花中提取出的倍半萜化合物进行鉴定,明确了其理化性质和化学结构,并通过药效学试验发现该组倍半萜化合物具有抗肿瘤、抗炎活性,可用于制备抗肿瘤药物、抗炎药物,且该组倍半萜化合物尤其对与阿尔兹海默病相关的炎症具有很好的药学活性,也可用于制备抗阿尔兹海默病药物。(The invention belongs to the technical field of medicines, and provides a group of sesquiterpene compounds, a preparation method and application thereof.)

1. A group of sesquiterpene compounds and tautomers and pharmaceutically acceptable salts thereof have the following structural formula:

compound 1:compound 2:

compound 3:

compound 5:

compound 7:

2. a process for the preparation of a set of sesquiterpenes according to claim 1, characterized in that: the method comprises the following steps:

(1) drying trilobate wedelia chinensis, and extracting with ethanol to obtain an extract;

(2) sequentially extracting the extracting solution by using a low-polarity solvent, a medium-polarity solvent and a high-polarity solvent;

(3) separating the medium-polarity layer by silica gel column chromatography, and performing gradient elution by using a medium-polarity-high-polarity solvent to obtain dry weight samples A and B of elution parts with a volume ratio of the medium-polarity solvent to the high-polarity solvent of 100:1 and 50: 1;

(4) carrying out silica gel column layer separation, ODS column chromatography separation and semi-preparative reverse phase HPLC separation on the sample A to obtain compounds 1, 2 and 3;

(5) and (3) carrying out silica gel column layer separation on the sample B, wherein the volume ratio of the polar solvent to the high-polar solvent is 50:1, performing ODS column chromatography separation and semi-preparative reverse phase HPLC separation on an elution part to obtain a compound 4;

(6) or carrying out silica gel column layer separation on the sample B, wherein the volume ratio of the medium-polarity solvent to the high-polarity solvent is 30: ODS column chromatography separation and semi-preparative reverse phase HPLC separation are carried out on the elution part 1 to obtain the compounds 5, 6, 7 and 8.

3. The production method according to claim 2, characterized in that: the low-polarity solvent is independently selected from at least one of hydrocarbon solvents such as cyclohexane, petroleum ether, n-hexane, isooctane, trimethylpentane, cyclopentane, heptane and the like.

4. The production method according to claim 2, characterized in that: the medium-polarity solvent is independently selected from at least one of ethyl acetate, chloroform, dichloromethane, diethyl ether, methyl formate, nitromethane, butyl acetate and isopropyl ether; the high-polarity solvent is at least one selected from n-butanol, methanol, tert-butanol, propanol, isopropanol, ethanol, acetone, tetrahydrofuran and pyridine.

5. The production method according to claim 2, characterized in that: the lower alcohol is C1-C6 alkyl alcohol.

6. The production method according to claim 2, characterized in that: the gradient elution sequence of the medium-polarity and high-polarity solvents in the step (3) is as follows: 100:1, 80:1, 50:1, 30:1, 20:1, 15:1, 10:1, 5:1, 3:1, 1:1, 0: 1.

7. The use of the sesquiterpene compounds 1-4 according to claim 1, tautomers thereof and pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

8. Use of the sesquiterpene compounds 5-8 according to claim 1 in the preparation of anti-inflammatory drugs, tautomers and pharmaceutically acceptable salts thereof.

9. The use of the sesquiterpene compounds 5-8 according to claim 1 in the preparation of anti-Alzheimer drugs, and tautomers and pharmaceutically acceptable salts thereof.

10. Use according to claim 9, characterized in that: the medicament for resisting the Alzheimer disease is any one of oral preparation, powder, granules, capsules, pills and tablets.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a group of sesquiterpene compounds, and a preparation method and application thereof.

Background

Inflammation is a defense reaction of living tissues with a vascular system to injury factors, most diseases are accompanied by inflammation, the inflammation can aggravate the occurrence and development of the diseases, and some chronic inflammations can cause the occurrence of tumors, so that the inflammation control and treatment are very important.

Tumor is a new organism formed by local histiocyte proliferation under the action of various tumorigenic factors, is one of the main killers threatening human health at present, and no effective cure medicine exists at present.

Alzheimer's Disease (AD) is a central neurodegenerative disorder with progressive cognitive impairment and memory impairment, with changes in mood and personality, that severely affects the performance and quality of life of patients. Nowadays the incidence of AD is increasing year by year. The main pathological features of AD are that a protein plaque formed by the deposition of extracellular beta-amyloid protein and intracellular microscopic related protein are over-phosphorylated to form neuron fiber tangles, and finally inflammation, oxidative stress, neuron death and the like are caused to cause a series of AD symptoms. Microglia (BV-2) are central immune cells that, in the activated state, inhibit beta-amyloid deposition and aggregation. Numerous studies have shown that various factors contribute to the activation of BV-2 and thus to the neuroinflammatory response, which plays an important role in the development of AD.

Natural drugs, especially those derived from plants, have a wide variety of chemical structures and biological activities, and have been a major source of diseases prevention and treatment in humans. Many drugs applied clinically are directly or indirectly derived from natural products, the natural products can be used not only as semi-synthetic precursors of drugs, but also as templates of chemical synthetic drugs, and provide a new idea for the design of new drugs, and the natural products have become one of the main sources for finding new drugs or lead compounds.

Wedelia trilobata (Wedelia trilobata) is a herb of Wedelia (Wedelia) in Compositae (Compositae), and is mainly used for treating snake bite, fish bite, diarrhea, kidney stone, cold and other diseases. Modern pharmacological experimental research also shows that wedelia trilobata has certain pharmaceutical activity, but specific active ingredients exerting effects, corresponding diseases and pharmacological mechanisms are still in an unknown state.

Disclosure of Invention

The invention aims to provide a group of sesquiterpene compounds and a preparation method and application thereof.

The structural formula of the group of sesquiterpene compounds provided by the invention is as follows:

the invention also provides a preparation method of the sesquiterpenoids, which comprises the following steps:

(1) drying trilobate wedelia chinensis, and extracting with ethanol to obtain an extract;

(2) sequentially extracting the extracting solution by using a low-polarity solvent, a medium-polarity solvent and a high-polarity solvent;

(3) separating the medium-polarity layer by silica gel column chromatography, and performing gradient elution by using a medium-polarity solvent and a high-polarity solvent to obtain dry weight samples A and B of an elution part with the volume ratio of the medium-polarity solvent to the high-polarity solvent being 100:1 and 50: 1;

(4) carrying out silica gel column layer separation, ODS column chromatography separation and semi-preparative reverse phase HPLC separation on the sample A to obtain compounds 1, 2 and 3;

(5) and (3) carrying out silica gel column layer separation on the sample B, wherein the volume ratio of the polar solvent to the high-polar solvent is 50:1, performing ODS column chromatography separation and semi-preparative reverse phase HPLC separation on an elution part to obtain a compound 4;

(6) or carrying out silica gel column layer separation on the sample B, and carrying out the separation on the polar solvent and the high-polar solvent at a volume ratio of 30: ODS column chromatography separation and semi-preparative reverse phase HPLC separation are carried out on the elution part 1 to obtain the compounds 5, 6, 7 and 8.

The low-polarity solvent is at least one selected from hydrocarbon solvents such as cyclohexane, petroleum ether, n-hexane, isooctane, trimethylpentane, cyclopentane and heptane.

Further, the medium-polarity solvent is at least one selected from ethyl acetate, chloroform, dichloromethane, diethyl ether, methyl formate, nitromethane, butyl acetate and isopropyl ether; the high-polarity solvent is selected from at least one of n-butanol, methanol, tert-butanol, propanol, isopropanol, ethanol, acetone, tetrahydrofuran, and pyridine.

Further, the lower alcohol is C1-C6 alkyl alcohol.

Further, the gradient elution sequence of the medium-polarity-high-polarity solvent in the step (3) is as follows: 100:1, 80:1, 50:1, 30:1, 20:1, 15:1, 10:1, 5:1, 3:1, 1:1, 0: 1.

The invention also provides application of the sesquiterpene compounds 1-4 and tautomers and pharmaceutically acceptable salts thereof in preparation of antitumor drugs.

The invention also provides application of the sesquiterpene compounds 5-8 and tautomers and pharmaceutically acceptable salts thereof in preparation of anti-inflammatory drugs.

The invention also provides application of the sesquiterpene compounds 5-8 and tautomers and pharmaceutically acceptable salts thereof in preparation of medicines for resisting Alzheimer disease.

Further, the medicament for resisting the Alzheimer disease is any one of oral preparation, powder, granules, capsules, pills and tablets.

Compared with the prior art, the invention extracts a group of new sesquiterpene compounds from wedelia trilobata, and identifies the new sesquiterpene compounds through physicochemical constants and modern spectroscopy, thereby defining the physicochemical properties and the chemical structure of the new sesquiterpene compounds. Pharmacodynamic tests show that the sesquiterpene compounds have antitumor and anti-inflammatory activities, can be used for preparing antitumor drugs and anti-inflammatory drugs, have good pharmaceutical activity on inflammation related to Alzheimer disease, and can also be used for preparing anti-Alzheimer disease drugs.

Drawings

FIGS. 1 to 3 are views of Compound 1¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 4 to 6 are views of Compound 2¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 7 to 9 are views of Compound 3¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 10 to 12 are views of Compound 4 in the order named¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 13 to 15 are views of Compound 5 in sequence¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 16 to 18 are views of 6 in the order of compounds¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 19 to 21 are views of Compound 7 in the order named¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIGS. 22 to 24 are views of Compound 8 in the order named¹H-NMR，¹³C-NMR, HR-ESI-MS spectrum;

FIG. 25 shows the results of Hochests staining experiments for the compounds 1 to 3 in example 2;

FIG. 26 shows the results of the experiments of Compounds 1-3 of example 2 for inhibiting the growth of cancer cells;

FIG. 27 shows the results of Western Blot experiment in example 2;

FIG. 28 shows the results of Western Blot experiment in example 3.

Detailed Description

The technical solution of the present invention will be described below with reference to specific examples.