CN110038041A - SIRT1 agonist and its application - Google Patents
SIRT1 agonist and its application Download PDFInfo
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- CN110038041A CN110038041A CN201910410704.9A CN201910410704A CN110038041A CN 110038041 A CN110038041 A CN 110038041A CN 201910410704 A CN201910410704 A CN 201910410704A CN 110038041 A CN110038041 A CN 110038041A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/484—Glycyrrhiza (licorice)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The present invention provides a kind of SIRT1 agonists, are the crystallized products of Z018A, include 3 ingredients, there are three characteristic peaks for HPLC test map tool.The agonist quality is stablized, and can significantly improve SIRT1 Level of Expression of Retinoic Acid, can be used for anti-aging.In addition, the present invention also provides based on the agonist pharmaceutical preparation and application etc..
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, can improve the present invention relates to the agonist of SIRT1 a kind of
The expression of SIRT1, can be used for anti-aging.
Background technique
The Z018A that the present inventor develops early stage is disclosed in Chinese patent ZL201610169121.8, and (its full text is included in this
Text reference) in, quality is stablized, and tool can be used for preventing or treating fatty liver there are three characteristic peak in HPLC test map
Damage and fat, reduction blood lipid level, and reduce inflammatory factor level.
After the patent disclosure, the present inventor finds no the new indication or otherwise improvement for Z018A
Report.For example, intracellular activation oxygen is considered as causing the main reason of cellular damage, and the accumulation of cellular damage is final
It will lead to cell ageing, and deacetylase silencing regulatory factor 1 (SIRT1) can alleviate cell by inhibiting NF- κ B access
Interior activation oxygen load, to slow down the aging of cell, therefore activation SIRT1 facilitates anti-aging (Hubbard B P etc.
.Trends Pharmacol Sci,2014,35(3):146-154).However, the prior art there is no it and anti-aging or
Associated report between SIRT1.
Nevertheless, the present inventor does not influence the research and development unpopularity of Z018A by the prior art, by grinding for a long time
Study carefully, surprisingly its crystallized product (ZAG019) is the agonist of SIRT1 a kind of, can be used for anti-aging.
Summary of the invention
Technical problems to be solved of the invention are to provide new SIRT1 agonist, can improve internal SIRT1 and express water
It is flat, it is used for anti-aging.In addition, the present invention also provides the pharmaceutical preparation of the agonist and preparation method and in medicine preparation
Using etc..
Specifically, in a first aspect, being the crystallized product of Z018A the present invention provides a kind of SIRT1 agonist.
Herein, term " SIRT1 agonist " refers to improve the substance of the expression of SIRT1 in vivo.The substance can
To be compound, it is also possible to composition.The SIRT1 agonist of first aspect present invention is named as HPLC test map, packet
It is a kind of composition containing three ingredients.
Herein, term " Z018A " refers to that the purification for the Radix Glycyrrhizae that Chinese patent ZL201610169121.8 is recorded mentions
Object is taken, it can be prepared by the following method:
(1) with after flooding Radix Glycyrrhizae, retain solid portion；
(2) solid portion that the alcohol leach step (1) with concentration greater than 85% (V/V) obtains retains liquid portion and does
It is dry；
(3) macropore is splined on after dissolving the desciccate that step (2) obtains with the alcohol that concentration is 50~57% (V/V) to inhale
Attached resin chromatography column collects the eluent eluted with the alcohol that concentration is 59~70% (V/V) and drying；With,
(4) polyamide is splined on after dissolving the desciccate that step (3) obtains with the alcohol that concentration is 30~60% (V/V)
Resin chromatography column is eluted with the alcohol that concentration is 30~60% (V/V), collects eluent.
It is preferred that alcohol is methanol and/or ethyl alcohol, preferably ethyl alcohol in the preparation method of Z018A.
It is also preferred that in step (2), concentration is greater than 90% (V/V), preferably greater than 93% (V/ in the preparation method of Z018A
V), such as 95% (V/V).
Further preferably in the preparation method of Z018A, in step (3), the concentration of the alcohol of dissolution is 53~56% (V/V), such as
55% (V/V)；And/or it is 60~62% (V/V) that the alcohol of elution, which obtains concentration, such as 60% (V/V).
In addition preferably in the preparation method of Z018A, in step (4), concentration be 40~50% (V/V), preferably 43~
48% (V/V), such as 45% (V/V).
It is preferred that the agonist of first aspect present invention is the alcohol crystal product of Z018A.That is, first aspect present invention swashs
Dynamic agent is that Z018A is crystallized in the solvent containing ethyl alcohol, then filters the product of acquisition.In a specific embodiment of the invention
In, the content of the ethyl alcohol is 50~55% (V/V).
It is preferred that the agonist of first aspect present invention can be prepared by the method included the following steps:
(5) after the preparation step (4) of above-mentioned Z018A, the eluent that step (4) is obtained is concentrated, and is preferably concentrated into institute
/ 5th~20 of effluent volume is stated, is preferably concentrated into 1/10th；With,
(6) ethyl alcohol is added in the concentrate obtained to step (5), so that the concentration of ethyl alcohol is 50~55% (V/V), stands knot
Crystalline substance, product collected by filtration, optionally again with the ethanol washing and drying that concentration is 15~25% (V/V).
The agonist of first aspect present invention is named as " ZAG019 ", including three kinds of ingredients.From HPLC test map
It sees, there are three characteristic peak, their retention time is detected with the HPLC of Z018A respectively to be schemed the agonist tool of first aspect present invention
Three characteristic peaks in spectrum are identical, but peak area is different.
It is preferred that the HPLC test map of the agonist of first aspect present invention has three characteristic peaks as shown in Figure 1.More
It is preferred that the ratio of these three characteristic peaks is also stable, for example, the peak area of these three characteristic peaks as shown in Figure 1 from left to right
The ratio between be 0.9~1.1:20~24:900~1100, in 1:22:977 or so.
In second aspect, the present invention provides the preparation methods of the agonist of first aspect present invention comprising to containing
The solution of Z018A is concentrated, is crystallized and the step of optional washing.
It is preferred that the method for second aspect of the present invention includes:
(5) after the preparation step (4) of above-mentioned Z018A, the eluent that step (4) is obtained is concentrated, and is preferably concentrated into institute
/ 5th~20 of effluent volume is stated, is preferably concentrated into 1/10th；With,
(6) ethyl alcohol is added in the concentrate obtained to step (5), so that the concentration of ethyl alcohol is 50~55% (V/V), stands knot
Crystalline substance, product collected by filtration, optionally again with the ethanol washing and drying that concentration is 15~25% (V/V).
More preferably in the preparation method of second aspect of the present invention, in step (6), the concentration of the ethyl alcohol for washing is
20% (V/V).
In the third aspect, the present invention provides pharmaceutical preparations comprising the agonist of first aspect present invention and pharmaceutically
Acceptable auxiliary material.Herein, term " pharmaceutically acceptable auxiliary material " include pharmaceutically acceptable carrier, excipient,
Diluent etc., they are compatible with active pharmaceutical ingredient.It is general to this field that pharmaceutical preparation is prepared with pharmaceutically acceptable auxiliary material
It is well known for logical technical staff.Pharmaceutical preparation of the invention include first aspect present invention composition as activity at
Point, by the composition and pharmaceutically acceptable adjuvant (carrier, excipient, dilute as would be known to one of ordinary skill in the art
Release agent and flavoring agent etc.) it combines, various preparations, preferably solid pharmaceutical preparation and liquid preparation are configured to, such as tablet, ball
Agent, capsule (including releasing pattern is released in sustained release or delay), pulvis (such as freeze dried powder), suspension, granule, tincture, sugar
Dosage forms and the various sustained-release dosage types such as agent, emulsion agent, suspension, injection are starched, so that it is suitble to various form of medication, such as oral,
Parenteral injection, mucous membrane, muscle, intravenous, subcutaneous, intraocular, intradermal or by skin etc. form of medication, most preferably mouth
Clothes.In a specific embodiment of the invention, the pharmaceutical preparation of third aspect present invention is liquid oral medicine.
In fourth aspect, the present invention provides the SIRT1 agonist of first aspect present invention in preparation for improving in vivo
Application in the drug of SIRT1 expression.The individual for improving expression is preferably aging individuals.Herein, individual can
To be mammal, such as mouse, preferably people.
At the 5th aspect, the present invention provides the SIRT1 agonist of first aspect present invention in preparation for anti-aging
Application in drug.
The beneficial effects of the present invention are: the present invention provides a kind of new SIRT1 agonists, can significantly improve in vivo
The expression quantity of SIRT1 is used for anti-aging；In addition, SIRT1 agonist quality of the invention is stablized, qualitative characteristics are hardly by sweet
The influence in careless source.
The present invention refers to existing open source literature, these documents are their full text in order to more clearly describe the present invention
Content is included in this paper, just looks like that repeated description herein has been excessively for their full text.
In order to make it easy to understand, below will present invention is described by specific drawings and examples.It needs to refer in particular to
Out, these descriptions are only exemplary description, and are not meant to limit the scope of the invention.Utilize the embodiment of the present invention
The method, it is also possible to obtain present invention others technical solution.According to the discussion of this specification, many changes of the invention
Changing, changing all is obviously for those skilled in the art.
Detailed description of the invention
Fig. 1 shows the HPLC testing result of ZAG019 of the invention.
Fig. 2 shows one group of western blot photo that each drug influences D- gal Aging rat model SIRT1,
It is wherein grouped are as follows: Normal group (Control), model group (Model), silibinin control group (Silibinin (100mg/
Kg)), ZAG019 low dose group (ZAG019 (5mg/kg)) and ZAG019 high dose group (ZAG019 (15mg/kg)).
Fig. 3 shows the statistical result that each drug influences D- gal Aging rat model SIRT1, wherein grouping are as follows:
Normal group (Control), model group (Model), silibinin control group (Silibinin (100mg/kg)), ZAG019
Low dose group (ZAG019 (5mg/kg)) and ZAG019 high dose group (ZAG019 (15mg/kg))；P < 0.01 *, relative to normal
Control group；#The He of p < 0.05##P < 0.01, relative to model group.
Specific embodiment
Plant material and chemical reagent in specific embodiment are the conventional material bought from market channel, wherein pharmacology
The relevant animal experiment that experiment has followed CFDA is guided.
The preparation of 1 ZAG019 of embodiment
The method for preparing Z018A referring generally to embodiment 1 in Chinese patent ZL201610169121.8 carries out, different
To collect polyamide to chromatograph column eluent, 60 DEG C of effluent volumes for being concentrated under reduced pressure into collection 1/10th after, be added
Ethyl alcohol after being in ethyl alcohol final concentration between 50~55% (V/V), stands crystallization, crystal is collected by filtration, with 20% (V/V) second
Alcohol washing, up to ZAG019 after drying.
Take a small amount of ZAG019, be dissolved in methanol, carry out HPLC detection, using Diamonsil C18 chromatographic column (4.6mm ×
250mm, 5 μm), 25 DEG C of column temperature, using -0.2% phosphate aqueous solution of methanol as mobile phase, flow velocity 0.8mL/min, Detection wavelength is
379nm carries out gradient elution with condition described in table 1.
Separate sources, each batch Radix Glycyrrhizae pass through above-mentioned purification, the yield of gained ZAG019 has sizable difference, still
Quality is stablized, and HPLC testing result is substantially all as shown in Figure 1, still show three characteristic peaks, these three peaks from left to right
The ratio between peak area is about 1:22:977.
Table 1: gradient elution table
The Antisenility Experiment of 2 ZAG019 of embodiment
The ZAG019 for taking the preparation method preparation according to embodiment 1, is administered aging model rat, studies it to SIRT1
Influence.
1, experimental drug
High dose ZAG019 and low dosage ZAG019: ZAG019, which is configured to concentration with 0.5%CMC-Na solution, is respectively
The solution of 1.5mg/ml and 0.5mg/ml.
Silibinin (Silibinin): silibinin is configured to concentration with 0.5%CMC-Na as the solution of 10mg/ml.
2, experimental animal
Wistar rat, male, weight 180-200g.Feeding environment: SPF grades of animal houses are freely ingested, and 12h illumination/
12h is dark.
3, experimentation
50 wistar rat adaptive feedings are randomly divided into Normal group (Control), mould after a week, according to weight
Type group (Model), silibinin control group (Silibinin (100mg/kg)), ZAG019 low dose group (ZAG019 (5mg/
Kg)) and ZAG019 high dose group (ZAG019 (15mg/kg)), every group 10.In addition to Normal group, remaining 4 groups rat neck
Dorsal sc injection D- galactolipin 120mg/kg；And isometric physiological saline is subcutaneously injected in Normal group；Normal group and
About 0.2ml 0.5%CMC-Na solution is administered in the rat oral gavage of model group；And silibinin control group, ZAG019 low dose group and
The rat of ZAG019 high dose group then distinguishes gastric infusion 100mg/kg silibinin, 5mg/kg ZAG019 and 15mg/kg
ZAG019 is injected with gastric infusion 1 time a day, continuous 56 days.It is deprived of food but not water after the last administration, puts to death rat after 16 hours,
It takes rat liver tissue to detect SIRT1 for western blot and calculates the SIRT1 expression of each group (with GAPDH for ginseng
According to).
4, experimental result
As a result as shown in Figures 2 and 3, administration D- galactolipin can significantly reduce SIRT1 expression；Compared with model group,
Each administration group has agonism to SIRT1, promote SIRT1 expression increase, all had compared with model group significant difference (p <
0.01 or p < 0.05), wherein ZAG019 is to the agonism of SIRT and its dosage correlation, but low dosage
The effect of ZAG019 has been over the effect of positive drug silibinin.
Claims (10)
1. a kind of SIRT1 agonist is the crystallized product of Z018A.
2. agonist described in claim 1 comprising three kinds of ingredients.
3. agonist described in claim 1, HPLC test map has three characteristic peaks as shown in Figure 1.
4. agonist as claimed in claim 3, wherein the ratio between the peak area of three characteristic peaks from left to right is 0.9~1.1:
20~24:900~1100, such as 1:22:977.
5. agonist described in claim 1 is the alcohol crystal product of Z018A.
6. the preparation method of any agonist of Claims 1 to 5 comprising carried out to the solution containing Z018A dense
The step of contracting, crystallization and optional washing.
7. pharmaceutical preparation comprising any agonist and pharmaceutically acceptable auxiliary material of Claims 1 to 5.
8. pharmaceutical preparation as claimed in claim 7 is oral preparation.
9. any SIRT1 agonist of Claims 1 to 5 is preparing the medicine for improving internal SIRT1 expression
Application in object.
10. application of any SIRT1 agonist of Claims 1 to 5 in the drug that preparation is used for anti-aging.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910410704.9A CN110038041B (en) | 2019-05-16 | 2019-05-16 | SIRT1 agonist and application thereof |
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| CN201910410704.9A CN110038041B (en) | 2019-05-16 | 2019-05-16 | SIRT1 agonist and application thereof |
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| CN110038041B CN110038041B (en) | 2021-06-08 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101176786A (en) * | 2006-11-08 | 2008-05-14 | 中国科学院上海生命科学研究院 | Method and composition for increasing insulin sensibility |
| CN105708891A (en) * | 2016-03-23 | 2016-06-29 | 北京慧宝源生物技术有限公司 | Drug composition for controlling and treating fatty liver of human body and application thereof |
| US20170042957A1 (en) * | 2014-04-16 | 2017-02-16 | Vital Solutions Swiss Ag | Mangifera indica as a sirtuin 1 activating agent |
| CN107028782A (en) * | 2016-02-04 | 2017-08-11 | 北京工商大学 | The purposes of isoliquiritigenin or isoliquiritin in the anti-aging cosmetics of high security are prepared |
-
2019
- 2019-05-16 CN CN201910410704.9A patent/CN110038041B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101176786A (en) * | 2006-11-08 | 2008-05-14 | 中国科学院上海生命科学研究院 | Method and composition for increasing insulin sensibility |
| US20170042957A1 (en) * | 2014-04-16 | 2017-02-16 | Vital Solutions Swiss Ag | Mangifera indica as a sirtuin 1 activating agent |
| CN107028782A (en) * | 2016-02-04 | 2017-08-11 | 北京工商大学 | The purposes of isoliquiritigenin or isoliquiritin in the anti-aging cosmetics of high security are prepared |
| CN105708891A (en) * | 2016-03-23 | 2016-06-29 | 北京慧宝源生物技术有限公司 | Drug composition for controlling and treating fatty liver of human body and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| HAN JY等: "Licochalcone Suppresses LXRα-Induced Hepatic Lipogenic Gene Expression through AMPK/Sirt1 Pathway", 《TOXICOLOGICAL RESEARCH》 * |
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