CN109806265A - A kind of new notoginsenoside preparation and application thereof - Google Patents
A kind of new notoginsenoside preparation and application thereof Download PDFInfo
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- CN109806265A CN109806265A CN201711152062.4A CN201711152062A CN109806265A CN 109806265 A CN109806265 A CN 109806265A CN 201711152062 A CN201711152062 A CN 201711152062A CN 109806265 A CN109806265 A CN 109806265A
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- dammarane
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- mixture
- notoginsenoside
- 25smdt
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Abstract
The invention belongs to pharmaceutical technology fields, are related to a kind of new notoginsenoside preparation and application thereof.This entitled 20 (R) -25- methoxyl groups-dammarane-3 beta to compound, 12 β, tri- pure and mild 20 (S) -25- methoxyl group of 20--dammarane-3 beta, 12 β, 20- triol [20 (R) -25-methoxyl-dammarane-3 β, 12 β, 20-triol (abbreviation 25Rmdt) and 20 (S) -25-me-thoxyl-dammarane-3 β, 12 β, 20-triol (abbreviation 25Smdt)].The compound of the present invention can be prepared using acid-hydrolysis method, alkali hydrolysis method and synthetic method, preparation method simple possible.Clinical feasible various dosage forms can be made in 25Rmdt and 25Smdt and their mixture (racemic modification) with pharmaceutically acceptable carrier, have shown that through research: the compound and its preparation have significant antitumor action, and any medicinal and health care product dosage form of various cancers treatment can be made for, it is mainly used in the prevention and treatment of malignant tumour, is had a extensive future.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of new notoginsenoside preparation and application thereof.
Background technique
Many scholars's research shows that notoginsenoside has apparent antitumor and immunoregulation effect, improves microcirculation and make
With, improve the multiple biological activities such as quality of life.But due to the more difficult absorption of natural notoginsenoside, and by saponin conversion and
The low polarity saponin that comes, or both derivative be prototype that natural notoginsenoside plays its drug effect.Therefore, related low polarity soap
Glycosides, or both derivative preparation and anti-tumor activity research it is very active, it has been found that they are with a variety of antitumor
While active, have no toxic side effect substantially.So far be found to have anti-tumor activity low polarity saponin, or both derivative
Have: notoginsenoside-Rg3、Rh2, C-K, Mc, PPD and 3 β, 12 β-dihydroxy -20 (22), 24 (25)-diene dammarane and 3 β, 6 α,
12 β-three hydroxyls -20 (22), 24 (25)-diene dammarane etc..Anti-tumor drug Shenyi capsule (the notoginsenoside-listed
Rg3), the anti-tumor drug that is being used for clinical and experimental study have notoginsenoside-Rh2With notoginsenoside-C-K.
25Rmdt and 25Smdt and their mixture (racemic modification) are the derivatives of PPD, do not find this two kinds so far
The report of compound and its mixture and preparation method thereof.
Summary of the invention
The purpose of the present invention is to provide a kind of new notoginsenoside preparations and application thereof.This to compound entitled 20
(R) -25- methoxyl group-dammarane-3 beta, 12 β, 20- tri- pure and mild 20 (S) -25- methoxyl groups-dammarane-3 beta, 12 β, 20- triol [20
(R) -25-methoxyl-dammarane-3 β, 12 β, 20-triol (abbreviation 25Rmdt) and 20 (S) -25-me-thoxyl-
Dammarane-3 β, 12 β, 20-triol (abbreviation 25Smdt)].
A pair of new Radix Notoginseng soap 25Rmdt and 25Smdt and their mixture (racemic modification) have significant antitumor
Effect, has broad application prospects,
25Rmdt and 25Smdt and their mixture (racemic modification) the preparation method is as follows: A: sour water solution I method: Radix Notoginseng
Total saposins, which are dissolved in acidic aqueous, carries out ultrasonic acidolysis, then passes through alkali neutralization, organic solvent extraction and silica gel column layer
25Rmdt and 25Smdt and their mixture (racemic modification) are obtained after analysis separation；B, sour water solution II method: i.e. arasaponin
It is dissolved in acidic aqueous and carries out ultrasonic sour water solution, then aqueous precipitation, be washed to neutral precipitating through silica gel column chromatography
25Rmdt and 25Smdt and their mixture (racemic modification) are obtained after separation；C, using chemically synthesized method, 25Rmdt
It is using 20 (R) and 20 (S) -25- hydroxyls-dammarane-3 beta, 12 β, 20- with 25Smdt and their mixture (racemic modification)
Triol (20 (R) and 20 (S) -25-OH-PPD) or their mixture (mixture (racemic modification)) under base catalysis with iodine first
Methylation reaction is carried out in alkane/anhydrous tetrahydro furan solvent and is obtained.D, synthetic method 2,25Rmdt and 25Smdt and their mixing
Body (racemic modification) is using 20 (R) and 20 (S) -25-OH-PPD or their mixture (mixture (racemic modification)) in alkali
Catalysis is lower to be obtained with reacting in dimethyl suflfate/anhydrous propanone solvent.E, using nuclear magnetic resonance spectrometry to gained 25Rmdt and
25Smdt and their mixture (racemic modification) carry out Structural Identification.
The arasaponin, referring to has all of dammarane's tetracyclic triterpene structural framework from Araliaceae Radix Notoginseng accessory
The root of plant, stem, leaf, flower (flower bud), fruit (slurry), the saponins compound contained in seed and in gynostemma pentaphylla.20 (R)
It can be made by arasaponin by acid, alkali, enzyme and microbial hydrolytic or conversion with 20 (S) -25-OH-PPD or their mixture
, it can also be made by the former notoginseng diol of 20 (R) and 20 (S)-by structure of modification.Arasaponin is using silica gel chromatography:
With what is obtained after the extraction of 10-99% ethyl alcohol, purification with macroreticular resin
The present invention uses alkaline hydrolysiss: being dissolved in low-alcohol solution with arasaponin, is made with alkali metal hydroxide
For hydrolysing agent carry out basic hydrolysis, then through peracid neutralize, organic solvent extraction, silica gel column chromatography separation after obtain 25Rmdt and
25Smdt and their mixture are dissolved in lower alcohol the progress acid under ultrasound condition using acid hydrolyzation, that is, arasaponin
Hydrolysis, then by alkali metal hydroxide neutralize, organic solvent extraction and the isolated 25Rmdt of silica gel column chromatography and
25Smdt and their mixture.Described lower alcohol is methanol；Organic solvent is petroleum ether, n-hexane, benzene, toluene, diformazan
Benzene, chloroform, methylene chloride, ether, ethyl acetate, one kind of n-butanol or in which 2-3 kind arbitrary proportion mixture；Described
Alkali metal hydroxide includes the hydroxide of sodium, potassium and calcium；The concentration of alkali metal hydroxide is 0.02-9%W/V.
The hydrolysis that acid is hydrolyzed to arasaponin carries out under ultrasound condition in acidic aqueous solution and organic solvent；Its
Part is as follows: the dosage 10-800g/L of arasaponin；
Lower alcohol is methanol, concentration 1-95%V/V；
Acid is hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, oxalic acid, glacial acetic acid, formic acid, and concentration is 0.2-9mol/L full with theirs
And acid；
Ultrasound condition: frequency: 20-70kHz；Power: 2.4-6KW；Time: 1-120 minutes；Water temperature: 15-100 DEG C；
Reaction solution sodium hydroxide or potassium hydroxide after hydrolysis neutralize, and the use of concentration are 0.2-9mol/L；Extraction
Organic solvent is petroleum ether, n-hexane, benzene,toluene,xylene, chloroform, methylene chloride, ether, ethyl acetate, n-butanol；
Column silica gel for chromatography granularity is 100-400 mesh；
Hydrolysis temperature are as follows: 4-100 DEG C, time 1min-5d.
In new antitumoral preparation provided by the present invention, with 25Rmdt and 25Smdt and their mixture (racemic
Body) it is effective component, total effective dose is 1-100mg/kg/d.
In new antitumoral preparation provided by the present invention, 25Rmdt and 25Smdt and their mixture (racemic modification)
The preparation of various pharmaceutical dosage forms can be made with any legal medicinal compounding agent and excipient.
In new antitumoral preparation provided by the present invention, 25Rmdt and 25Smdt and their mixture (racemic modification)
It can be different with any chemotherapeutic currently on the market, biological agent, including steroids, alkylating agents, platinum class, anti-metabolism, topology
Structure enzyme inhibitor class, induction differentiation class, neoplasm growth class, improves immunity of organism class and other drugs, system at anti-microfilament microtubules class
For at compound preparation.
In new antitumoral preparation provided by the present invention, preparation formulation is oral, injection or Topical application forms.
In new antitumoral preparation provided by the present invention, peroral dosage form includes tablet, pulvis, suspension, emulsion, glue
Capsule, granule, sugar coated tablet, pill, liquid, syrup and limonada etc..
In new antitumoral preparation provided by the present invention, injection type includes aqua, freeze-dried powder, vein emulsion, more
Phase plasmalogen preparation, venous microemulsion, suspension etc..
In new antitumoral preparation provided by the present invention, Topical application forms include ointment, solid, suspension, aqua,
Pulvis, paste, suppository, aerosol, opoultice, liniment, enema and emulsion etc..
The present invention provides 25Rmdt and 25Smdt compound and their mixtures, and can make two kinds of compounds and
Its mixture is applied in anti-tumor agent.New approach is provided to be antitumor.
Specific embodiment
Below with reference to embodiment, the present invention will be further described
Embodiment: sodium hydroxide hydrolysis method prepares 25Rmdt and 25Smdt and their mixture (racemic modification)
Radix Notoginseng fruit total saponin 10g is weighed, the methanol that 1000ml naoh concentration is 2.5mol/L, concentration is 80% is dissolved in
For 24 hours, with 2.5mol/L hydrochloric acid neutralization reaction liquid, methanol is recovered under reduced pressure in heated in water solution back hydrolysis, is extracted and is reacted with chloroform
Liquid, chloroform is mutually washed, anhydrous sodium sulfate is dry, is evaporated collection residue, through silica gel column chromatography separation, petroleum ether: acetic acid second
Ester (10: 1-1: 1) gradient elution obtains 86 flow points, and flow point 52-55 obtains 25Rmdt after re-crystallizing in ethyl acetate；Flow point 56-58
Merge after TLC is checked, obtains the mixture (racemic modification) of 25Rmdt and 25Smdt after removing solvent after re-crystallizing in ethyl acetate；
Flow point 59-62 merges through after TLC is checked, 25Smdt is obtained after re-crystallizing in ethyl acetate.
Claims (3)
1. a kind of new notoginsenoside preparation and application thereof, it is characterised in that: the Radix Notoginseng soap is 20 (R) -25- methoxyl groups -
Dammarane-3 beta, 12 β, 20- tri- pure and mild 20 (S) -25- methoxyl groups-dammarane-3 beta, 12 β, 20- triol, abbreviation 25Rmdt and
25Smdt, the mixture are the mixture of 25Rmdt and 25Smdt racemic modification.
2. a kind of new notoginsenoside preparation and application thereof as described in claim 1, it is characterised in that: including following method:
A: sour water solution I method: arasaponin, which is dissolved in acidic aqueous, carries out ultrasonic acidolysis, then passes through alkali neutralization, You Jirong
It is obtained after agent extraction and silica gel column chromatography separation；B, sour water solution II method: i.e. arasaponin be dissolved in acidic aqueous into
Row ultrasound sour water solution, then aqueous precipitation, is washed to neutral precipitating and obtains after silica gel column chromatography separates；C, it is closed using chemistry
At method, using 20 (R) and 20 (S) -25- hydroxyls-dammarane-3 beta, 12 β, 20- triol (20 (R) and 20 (S) -25-OH-
PPD) or their mixture obtains under base catalysis with methylation reaction is carried out in iodomethane/anhydrous tetrahydro furan solvent；D,
Synthetic method 2, using 20 (R) and 20 (S) -25-OH-PPD or their mixture under base catalysis with dimethyl suflfate/anhydrous third
It reacts and obtains in ketone solvent；E, Structural Identification is carried out to gained compound using nuclear magnetic resonance spectrometry.
3. the new notoginsenoside preparation and application thereof of one kind according to claim 2, it is characterised in that: the Radix Notoginseng is total
Saponin(e refers to root, stem, leaf, the Hua Huo of all plants for having dammarane's tetracyclic triterpene structural framework from Araliaceae Radix Notoginseng accessory
The saponins compound contained in title flower bud, fruit and slurry, seed and in gynostemma pentaphylla；20 (R) and 20 (S) -25-OH-PPD
Or their mixture can be obtained by acid, alkali, enzyme and microbial hydrolytic or conversion by arasaponin, can also by 20 (R) and
20 (S)-original notoginseng diol is made by structure of modification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711152062.4A CN109806265A (en) | 2017-11-19 | 2017-11-19 | A kind of new notoginsenoside preparation and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711152062.4A CN109806265A (en) | 2017-11-19 | 2017-11-19 | A kind of new notoginsenoside preparation and application thereof |
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| CN109806265A true CN109806265A (en) | 2019-05-28 |
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| CN201711152062.4A Pending CN109806265A (en) | 2017-11-19 | 2017-11-19 | A kind of new notoginsenoside preparation and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903340A (en) * | 2019-12-09 | 2020-03-24 | 沈阳药科大学 | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof |
| CN115669673A (en) * | 2022-08-18 | 2023-02-03 | 澳门大学 | Application of notoginsenoside Fe and/or notoginsenoside Fd in preparation of plant source bactericide and prevention and treatment of agricultural fungal diseases |
-
2017
- 2017-11-19 CN CN201711152062.4A patent/CN109806265A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903340A (en) * | 2019-12-09 | 2020-03-24 | 沈阳药科大学 | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof |
| CN110903340B (en) * | 2019-12-09 | 2022-03-01 | 沈阳药科大学 | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof |
| CN115669673A (en) * | 2022-08-18 | 2023-02-03 | 澳门大学 | Application of notoginsenoside Fe and/or notoginsenoside Fd in preparation of plant source bactericide and prevention and treatment of agricultural fungal diseases |
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Application publication date: 20190528 |