CN107536840A - The Sirt1 inhibitor of one kind containing 20 (R) ginsenoside Rh 1s and its preparation method and application - Google Patents
The Sirt1 inhibitor of one kind containing 20 (R) ginsenoside Rh 1s and its preparation method and application Download PDFInfo
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- CN107536840A CN107536840A CN201710966491.9A CN201710966491A CN107536840A CN 107536840 A CN107536840 A CN 107536840A CN 201710966491 A CN201710966491 A CN 201710966491A CN 107536840 A CN107536840 A CN 107536840A
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Abstract
The invention provides a kind of Sirt1 inhibitor 20 (R) ginsenoside Rh 1, the compound is isolated from the smelly ginseng of Yunnan production.Pharmaceutical composition present invention also offers the preparation method of the compound and containing the compound；Invention further provides the compound suppress Sirt1 in terms of activity, prompt its with the value in Sirt1 relevant diseases.
Description
Technical field
The invention belongs to chemical medicine field, is related to 20 (R)-ginsenoside Rh 1s and its is treated in preparation related to Sirt1
Application in the medicine of disease.
Background technology
(the silent mating type information regulation 2 of silent message regulatory factor 1
Homolog-1, Sirt1) it is a kind of nucleoprotein being widely present in mammalian cell, mainly by histone, transcription
The factor and other protein modified lysine residues carry out the expression of deacetylation and regulatory gene, and then wide participation aliphatic acid
The physiological activities such as oxidation, stress tolerance, insulin secretion, Apoptosis and aging, these physiological activities and type-II diabetes, the heart
Vascular diseases,Metabolic syndrome, inflammation, tumour and aging etc. it is closely related.Its correlation function is mainly reflected in following side
Face：(1) SIRT1 and energetic supersession aspect：SIRT1 can cooperate with Peroxisome proliferator-activators γ (PPAR- γ)
Stimulating factor a (PGC-1a) and Hepatocyte nuclear factor 4 a (HNF4a) are combined into a kind of albumen composition, in NAD presences,
SIRT1 activates HNF4a by deacetylation PGC-1a, so as to adjust the transcription of gluconeogenesis related gene, and then strengthens liver sugar
Heteroplasia.On the other hand, SIRT1 is by combining the upper 2 auxilins nuclear receptor co-suppression albumen (nuclear of PPAR- γ
Receptor corepressor, NCoR) and retinoic acid and Thyroid Hormone Receptors silence mediator protein (silencing
Mediator ofretinoid and hormone receptor, SMRT) suppress PPAR- gamma activities, and then in energy intake
During reduction, promote the lipid mobilization in white adipose tissue.(2) SIRT1 and insulin secretion:SIRT1 is by suppressing uncoupling
Albumen 2 (UCP-2) promotes pancreas islet b cells secrete insulins.UCP-2 makes line grain as the transport protein on mitochondrial inner membrane
Oxidative phosphorylation uncoupling in body respiration.Because energy is discharged with form of thermal energy during this, reduce ATP synthesis,
Now the intracellular ATP/ADP ratios of β reduce.K+ channel openers sensitive ATP are affected by it under caused intracellular [Ca2+]
Drop, it is suppressed that cell exocytosis, reduce insulin releasing.(3) SIRT1 and cell survival:SIRT1 can be with multiple protein phase
Interaction, original research think that SIRT1 major function is that Apoptosis and aging are reduced under stressed condition, increase cell survival
Rate.SIRT1 can negative regulation tumor suppressor p53-this is a kind of nonhistones substrates of the SIRT1 found earliest, SIRT1 is by p53
In 382 Lys residue deacetylations, reduce p53 and DNA cis element adhesions, reduce by the Apoptosis of its induction.Cause
This, SIRT1 is also regarded as a kind of potential tumour excitement.(4) SIRT1 and tumor multi-medicine drug-resistant:SIRT1 is many resistance to
High expression in the tumor line of medicine.Recent research indicate that effects of the SIRT1 in tumor drug resistance mainly may can be targetted and adjusted with it
It is related to FOXO3a activation to save tumor suppressor p53, p73, E2F1.In other words, acetyl is removed in the SIRT1 transcription factors relied on
Change for during regulatory gene expression, cell to avoid proliferative block and the cell death of caused by chemotherapeutic medicines.In a word, Sirt1
Function it is more complicated, it can be with deacetylation histone, can be with many important transcription factors of deacetylation and regulation egg
In vain, so as to regulating and controlling various biological process.
Radix Codonopsis is campanulaceae of the genus codonopsis, and a kind of plant for belonging to Codonopsis is commonly called as in Yunnan as smelly ginseng, Yunnan ginseng
For many years, find that it is really Radix Codonopsis (Codonopsis pilosula) by authority's identification, only because it is grown in Yunnan Low Latitude height
The particular surroundings of height above sea level and nature and flavor change occurs, function has dramatically different compared with other areas, and such as taking can fart frequency after smelly ginseng
Frequently, traditional north production Radix Codonopsis does not have this function.The Sirt1 inhibitor that the present invention therefrom has found has no report.
The content of the invention
It is an object of the invention to provide medical compounds 20 (R)-ginsenoside Rh 1, the medicine of 20 (R)-ginsenoside Rh 1s
Compositions, described pharmaceutical composition include 20 (R)-ginsenoside Rh 1s or its pharmaceutically acceptable derivates and its esters.
In order to realize the above-mentioned purpose of the present invention, the invention provides following technical scheme：
A kind of Sirt1 inhibitor, described active ingredient are 20 (R)-ginsenoside Rh 1s.
The pharmaceutical composition of 20 (R)-ginsenoside Rh 1s is included, described pharmaceutical composition includes 20 (R)-ginsenoside Rh 1s
Or its pharmaceutically acceptable derivates and its esters, and at least one carrier pharmaceutically.
Pharmaceutical composition as mentioned, described pharmaceutical composition are pharmaceutical preparation, by 20 (R)-ginsenoside Rh 1s or its medicine
Acceptable derivates and its esters form as active component and pharmaceutically acceptable excipient on.
The preparation method of 20 (R)-ginsenoside Rh 1s, this method are：
Take and dry smelly ginseng, (78L × 3 × 3h) are extracted with 80% alcohol reflux after crushing, extract solution obtains after merging concentration
Total extract.Total extract is extracted with ethyl acetate 3 times after being suspended with water, obtains water section and ethyl acetate extraction part respectively, wherein
Ethyl acetate extract row MCI gel CHP 20P posts (methanol-water, 35%-100%), gradient elution, obtain 10 component C1-
C10, C5 separate through Sephadex LH-20 (MeOH) gel filtration chromatography, obtain 5 components, C51-C55, wherein C52 are through RP-18 posts
(methanol-water, (11:9,13:7,15:9,17:3,19:1,1:0) C521-C524) is obtained, 4 components, C523 is through Sephadex
LH-20 (MeOH) gel obtains 4 components, C5231-C5234, wherein C5232 through RP-18 posts (methanol-water, (9:11,11:9,
13:7,15:9,17:3,19:1,1:0) C52321-C52328,8 components) are obtained, C52326 prepares HPLC (acetonitrile/waters through half
(0.05% formic acid) 40:60) 20 (R)-ginsenoside Rh 1s are purified to obtain.
20 (R)-ginsenoside Rh 1s answering in the medicine for preparing treatment Sirt1 relevant diseases as Sirt1 inhibitor
With.
Further, described pharmaceutical composition is pharmaceutical preparation, and it is 20 (R)-ginsenoside Rh 1s or it pharmaceutically may be used
The derivative and its esters of receiving form as active component and pharmaceutically acceptable excipient.
Wherein solid pharmaceutical preparation includes：Tablet, capsule, pill, granule etc.；Semisolid preparation includes ointment, suppository
Deng；Liquid preparation includes：Solution, injection, spray etc.；Eye-drops preparations includes：Eye drops, gel for eye etc..
20 (R)-ginsenoside Rh 1 of the present invention, its preparation method are：
Take and dry smelly ginseng 13kg, extract (78L × 3 × 3h) with 80% alcohol reflux after crushing, extract solution merges concentration
Total extract is obtained afterwards.Total extract is extracted with ethyl acetate 3 times after being suspended with water, obtains water section and ethyl acetate extraction part respectively.
Wherein ethyl acetate extract (about 350g) row MCI gel CHP 20P posts (methanol-water, 35%-100%), gradient elution, obtain 10
Individual component (C1-C10).C5 (8.5g) separates through Sephadex LH-20 (MeOH) gel filtration chromatography, obtains 5 components, C51-
C55.Wherein C52 (5.5g) through RP-18 posts (methanol-water, (11:9,13:7,15:9,17:3,19:1,1:0) C521-) is obtained
C524,4 components.C523 (1.9g) obtains 4 components, C5231-C5234 through Sephadex LH-20 (MeOH) gel.Wherein
C5232 (1.6g) through RP-18 posts (methanol-water, (9:11,11:9,13:7,15:9,17:3,19:1,1:0) C52321-) is obtained
C52328,8 components.C52326 (156mg) prepares HPLC (acetonitrile/waters (0.05% formic acid) 40 through half:60) purify 20
(R)-ginsenoside Rh 1 (8.3mg).
Further, 20 described (R)-ginsenoside Rh 1s be from Yunnan produce Radix Codonopsis or other contain the natural of the composition
Obtained in source.
Beneficial effects of the present invention：
1. 20 (R)-ginsenoside Rh 1 of the present invention separation identification from Yunnan production Radix Codonopsis (smelly ginseng) obtains.
2. 20 (R)-ginsenoside Rh 1 of the present invention has the effect for suppressing Sirt1.
Brief description of the drawings
Fig. 1 is that compound suppresses Sirt1 activity tests result (n=3)., should using Graph prism5 statistics softwares
With the statistical method of one-way analysis of variance, continuous data is with mean ± standard deviationRepresent, concentration for nicotinamide is
100 μM, the * p compared with blank group<0.05, * * p<0.01, * * * p<0.001.
Embodiment
Below in conjunction with the accompanying drawings, with embodiments of the invention, the invention will be further described.But this hair is not limited with this
It is bright.
Embodiment 1
The extraction separation of 20 (R)-ginsenoside Rh 1s and Structural Identification：
Take and dry smelly ginseng 13kg, extract (78L × 3 × 3h) with 80% alcohol reflux after crushing, extract solution merges concentration
Total extract is obtained afterwards.Total extract is extracted with ethyl acetate 3 times after being suspended with water, obtains water section and ethyl acetate extraction part respectively.
Wherein ethyl acetate extract (about 350g) row MCI gel CHP 20P posts (methanol-water, 35%-100%), gradient elution, obtain 10
Individual component (C1-C10).C5 (8.5g) separates through Sephadex LH-20 (MeOH) gel filtration chromatography, obtains 5 components, C51-
C55.Wherein C52 (5.5g) through RP-18 posts (methanol-water, (11:9,13:7,15:9,17:3,19:1,1:0) C521-) is obtained
C524,4 components.C523 (1.9g) obtains 4 components, C5231-C5234 through Sephadex LH-20 (MeOH) gel.Wherein
C5232 (1.6g) through RP-18 posts (methanol-water, (9:11,11:9,13:7,15:9,17:3,19:1,1:0) C52321-) is obtained
C52328,8 components.C52326 (156mg) prepares HPLC (acetonitrile/waters (0.05% formic acid) 40 through half:60) purify 20
(R)-ginsenoside Rh 1 (8.3mg).
Compound structure identification is as follows：
Compound 20 (R)-ginsenoside Rh 1：20(R)-ginsenoside-Rh1:yellowish gum；C36H62O9；1H
NMR(400MHz,methanol-d4)δH:5.11,4.36,4.11,3.83,3.65,3.56,3.28,3.11,3.20,2.08,
1.88,1.74,1.67,1.63,1.57,1.51,1.45,1.33,1.25,1.12,1.11,1.00,0.99,0.95.13C NMR
(150MHz,methanol-d4)δC:132.0(C-25),125.9(C-24),105.5(glc-1),81.0(glc-3),79.8
(C-3),79.1(glc-5),77.7(C-6),75.5(glc-2),74.6(C-20),71.9(glc-4),71.7(C-12),
62.9(glc-6),61.8(C-5),52.6(C-14),50.8(C-17),50.8(C-9),49.2(C-13),45.3(C-7),
43.3(C-22),41.8(C-8),40.5(C-4),40.4(C-10),40.2(C-1),31.8(C-11),31.4(C-15),
31.4(C-28),27.6(C-2),27.2(C-16),25.9(C-26),22.8(C-23),22.3(C-21),17.8(C-19),
17.7(C-27),17.5(C-18),17.3(C-30),16.1(C-29).
Embodiment 2
20 (R)-ginsenoside Rh 1 (qlxz-38e) of the present invention suppresses Sirt1 active testings：
Using Sirt1Fluorometric Drug Discovery Kit with detection compound to Sirt1 external activities
Influence.First, (the 1U=1pmolmin containing 0.5U is prepared-137 DEG C of at) Sirt1 (in addition to blank group), 1000 μm of olL- 1NAD+, 100 μm of olL-1Deacetylase substrate, SIRT1 experiment buffer solutions (50mmolL-1Tris-HCl,pH 8.0,
137mmol·L-1NaCl,2.7mmol·L-1KCl,1mmol·L-1MgCl2,1mg·ml-1BSA test system).Experimental group
Compound to be detected is added, blank group adds the solvent of equivalent dissolved compound with control group；Add the test body prepared
System, it is 25 μ L to make the cumulative volume of addition compound to be detected and test system.30min is incubated under the conditions of 37 DEG C after each experiment
1 × Fluor de Lys developer solution are added in hole and (contain 2mmolL-1Niacinamide) 25 μ L terminating reactions,
Reaction is carried out in the orifice plate of halfth area 96.Multi-function microplate reader 360nm exciting lights, 460nm launches measures each hole fluorescence under optical condition
Value.
Embodiment 3：
Compound 20 (R)-ginsenoside Rh 1 in embodiment 1, routinely method add solvent for injection, refined filtration, after embedding sterilizing
It can be made into parenteral solution.
Embodiment 4：
Compound 20 (R)-ginsenoside Rh 1, is dissolved in sterile water for injection in embodiment 1, with sterile funnel mistake
Filter, dispense, sterile seal produces powder-injection after frozen drying.
Embodiment 5：
Compound 20 (R)-ginsenoside Rh 1 in embodiment 1, routinely method be equipped with various pharmaceutic adjuvants can be made into tablet or
Capsule.
, as active constituents of medicine, several Typical excipients are used using compound 20 (R)-ginsenoside Rh 1 in embodiment 1
Agent is conventionally made every or every capsule and contains medicine as the adjunct ingredient for preparing composition of medicine tablet or capsule
Thing composition 10-300mg sample.
Claims (7)
1. a kind of Sirt1 inhibitor, it is characterised in that described active ingredient is 20 (R)-ginsenoside Rh 1s.
2. include the pharmaceutical composition of 20 (R)-ginsenoside Rh 1s, it is characterised in that described pharmaceutical composition includes 20 (R)-people
Join saponin(e Rh1 or its pharmaceutically acceptable derivates and its esters, and at least one carrier pharmaceutically.
3. pharmaceutical composition as claimed in claim 2, it is characterised in that described pharmaceutical composition is pharmaceutical preparation, by 20
(R)-ginsenoside Rh 1 or its pharmaceutically acceptable derivates and its esters are as active component and pharmaceutically acceptable tax
Shape agent forms.
4. the preparation method of 20 (R)-ginsenoside Rh 1s, it is characterised in that this method is：
Taking and dry smelly ginseng, 78L × 3 × 3h is extracted with 80% alcohol reflux after crushing, extract solution obtains total extract after merging concentration,
Total extract is extracted with ethyl acetate 3 times after being suspended with water, obtains water section and ethyl acetate extraction part, wherein ethyl acetate respectively
Position row MCI gel CHP 20P posts, methanol-water, 35%-100%, gradient elution, obtain 10 component C1-C10；C5 is passed through
Sephadex LH-20MeOH gel filtration chromatographies separate, and obtain 5 component C51-C55；Wherein C52 is through RP-18 posts, methanol-water,
11:9,13:7,15:9,17:3,19:1,1:0 obtains C521-C5244 component；C523 obtains through Sephadex LH-20MeOH gels
4 component C5231-C5234；Wherein C5232 is through RP-18 posts, methanol-water, and 9:11,11:9,13:7,15:9,17:3,19:1,
1:0 obtains C52321-C523288 component；C52326 prepares HPLC, the formic acid 40 of acetonitrile/water 0.05% through half:60 purify 20
(R)-ginsenoside Rh 1.
5. 20 (R)-ginsenoside Rh 1s answering in medicine of the treatment with Sirt1 relevant diseases is prepared as Sirt1 inhibitor
With.
6. application of 20 (the R)-ginsenoside Rh 1s in Sirt1 activators are prepared.
7. application of 20 (the R)-ginsenoside Rh 1s in medicine of the treatment with Sirt1 relevant diseases is prepared.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456383A (en) * | 2018-12-04 | 2019-03-12 | 长春中医药大学 | A kind of 20(R)-ginsenoside Rh1Preparation method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689552A (en) * | 2004-04-19 | 2005-11-02 | 日本日光化学株式会社 | Skin ageing resisting cosmetics and its production method |
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2017
- 2017-10-17 CN CN201710966491.9A patent/CN107536840A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689552A (en) * | 2004-04-19 | 2005-11-02 | 日本日光化学株式会社 | Skin ageing resisting cosmetics and its production method |
Non-Patent Citations (1)
| Title |
|---|
| LI-YUAN MA等: "New SIRT1 activator from alkaline hydrolysate of total saponins in the stems-leaves of Panax ginseng", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456383A (en) * | 2018-12-04 | 2019-03-12 | 长春中医药大学 | A kind of 20(R)-ginsenoside Rh1Preparation method |
| CN109456383B (en) * | 2018-12-04 | 2021-06-22 | 长春中医药大学 | 20(R) -ginsenoside Rh1Preparation method of (1) |
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