Extraction method, product and application of caffeoylquinic acid compounds

A technique of caffeoylquinic acid and extraction method, applied in the field of natural medicinal chemistry, can solve the problems of frequent subcutaneous administration, hepatitis B virus infection threatening public health, drug resistance, etc., and achieves significant anti-hepatitis B virus effect and normal cytotoxicity. Low, moderately effective doses

Active Publication Date: 2021-03-16
SHENZHEN PEOPLES HOSPITAL +1
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] At present, the control of HBV is mainly based on vaccination prevention. Although the vaccine is effective, hepatitis B virus infection is still a problem that threatens public health. The current drug treatment effect cannot meet the actual needs
At present, the Western medicines approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis B virus are divided into two categories: one is immunomodulators, including interferon α (IFN-α) and polyethylene glycol interference. α, which inhibits viral replication by activating the JAK-STAT signaling pathway. However, this type of drug has the disadvantages of frequent subcutaneous administration, many adverse reactions, and high cost. Therefore, it is rarely used clinically; the other type is nucleoside Analogs and nucleotide analog prodrugs, the former including vidarabine, lamivudine, famciclovir, adefovir, telbivudine and entecavir, the latter including adefovir dipivoxil and fumaric acid Tenofovir disoproxil, etc.; this type of drug can directly act on viral reverse transcriptase to block the replication of hepatitis B virus
However, although nucleoside drugs have good curative effect in the short term, the course of treatment is not clear, and they are prone to relapse after drug withdrawal, requiring lifelong treatment
This is because nucleoside analogs inhibit the replication of hepatitis B virus in the cytoplasmic environment, but have no effect on the ccc DNA pool in the nucleus, and long-term medication will lead to problems such as virus mutation and drug resistance

Method used

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  • Extraction method, product and application of caffeoylquinic acid compounds
  • Extraction method, product and application of caffeoylquinic acid compounds
  • Extraction method, product and application of caffeoylquinic acid compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0082] The extraction of four kinds of new natural caffeoylquinic acid compounds of embodiment 1

[0083] At room temperature, take 6.5kg of dried honeysuckle, use 75% ethanol to carry out multiple cold soaking and percolation extraction, combine the extracts, then recover the solvent under reduced pressure at 55°C, and concentrate to obtain 1500g of ethanol extract; The ethanol extract was suspended in water, and then extracted with cyclohexane, ethyl acetate, and n-butanol respectively to obtain 130.3g cyclohexane extract LJH, 93.7g ethyl acetate extract LJE, and 199.8g n-butyl Alcoholic extract LJB.

[0084] Get 83.0g of said ethyl acetate extract LJE, dissolve it with chloroform and methanol, mix the sample with 120g column chromatography silica gel (100-200 mesh), dissolve the silica gel column with dichloromethane, and equilibrate with dichloromethane The column does not drop down to the silica gel surface, and the sample is loaded by dry method, and then successively u...

Embodiment 2

[0090] The characterization of embodiment 2 caffeoylquinic acid compounds a, b, c, d

[0091] Characterization of caffeoylquinic acid compound a

[0092] The caffeoylquinic acid compound a provided by the present invention is a yellow amorphous powder, see Figure 7 , HR-ESI-MS (negative) gives quasi-molecular ion peak [M-H] - m / z 547.1627, suggesting a molecular weight of 548; binding 1 H and 13 C NMR confirmed its molecular formula as C 26 h 28 o 13 , with a calculated unsaturation of 18.

[0093] see Figure 1~6 , combined with Table 1, in 1 H NMR, δ H 3.76(1H,s), 5.03(1H,m), 5.14(1H,m) and δ H 1.98(3H,m) and 2.16(1H,d,J=11.0Hz) and δ H 3.60 (3H, m) suggests that the compound is a 4,5-disubstituted methyl quinic acid derivative, 13 δ on C NMR C 72.90(C-1), 35.46(C-2), 67.47(C-3), 71.07(C-4), 70.33(C-5), 34.82(C-6), 174.10(C-7), 52.11 (7-OCH 3 ) displacement signal also confirmed the above judgment. also, 1 δ of ABX system on H NMR H 7.05(1H, s), 7.00...

Embodiment 3

[0107] Example 3 In vitro cytotoxicity test of caffeoylquinic acid compounds a, b, c, d

[0108] The inventors conducted an in vitro cytotoxicity test on four natural caffeoylquinic acid compounds, and the cell lines used were HepG 2 cells and HepG 2.2.15 cells. HepG 2.2.15 cells are HepG 2 cells stably transfected with HBV genes, carrying the whole HBV genome, so they can carry out virus replication and stably secrete infectious virus particles, HBsAg and HBeAg.

[0109] MTT method: Inoculate HepG 2 cells and HepG 2.2.15 cells in a 96-well cell culture plate, 200 μL per well (containing 10×10 4 tumor cells), at 37°C, 5% CO 2 In the incubator, and in the DMEM medium containing 10%FBS, culture 24h, add the compound of the present invention (being caffeoylquinic acid compound a , b, c, d), continue to cultivate for 48h; add 20μL of MTT (5mg / mL) 4h before the end of the experiment, and continue to culture at 37°C, 5% CO 2 Incubate under the conditions for 4 hours, add 150 μL o...

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Abstract

The invention relates to the technical field of natural medicinal chemistry, particularly relates to an extracting method of a caffeoylquinic acid compound and product, relates to four caffeoylquinicacid compounds, and relates to application of the four caffeoylquinic acid compounds in preparation of drug for treating hepatitis B. The extracting method of the caffeoylquinic acid compound is simple to operate, economical, and environmentally friendly; the caffeoylquinic acid compounds a-d are natural small molecule compounds and are low in toxicity to normal cells and low in side effects; thehepatitis B resisting effect is obvious at the concentration less than cell toxicity concentration, so that a novel treatment drug and a treatment route are provided to patients with hepatitis B; thecaffeoylquinic acid compounds a-d have the advantages of being proper in effective dose, obvious in treatment effect, and small in toxic and side effects, and have good medicinal prospect.

Description

technical field [0001] The present invention relates to the technical field of natural medicinal chemistry, in particular to the extraction method of caffeoylquinic acid compounds, and to 4 kinds of caffeoylquinic acid compounds, and also to the use of these 4 kinds of caffeoylquinic acid compounds in the preparation and treatment of Application in hepatitis medicine. Background technique [0002] Hepatitis B (hepatitis B) is a disease caused by the infection of Hepatitis B virus (HBV), which is a worldwide infectious disease that seriously threatens human health. Viral hepatitis B can not only lead to acute and chronic hepatitis B infection, but also is related to 75% to 90% of primary liver cancer. HBV mainly exists in liver cells, and damages liver cells, causing inflammation, necrosis, and fibrosis of liver cells. In severe cases, it can lead to liver cirrhosis and hepatocellular carcinoma, which brings huge social and economic burdens. [0003] According to the survey...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/48C07C67/58C07C67/56C07C69/757A61K31/216A61P31/20
CPCA61P31/20C07B2200/07C07C67/48C07C67/56C07C67/58C07C69/757C07C2601/14
Inventor 曾小斌葛岚岚万浩强李洁媚张柯达吴伟刚邹小停吴诗品周伯平
Owner SHENZHEN PEOPLES HOSPITAL
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