CN102516343A - Novel antitumor compound ginsenoside Rh2 derivative and preparation thereof - Google Patents
Novel antitumor compound ginsenoside Rh2 derivative and preparation thereof Download PDFInfo
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- CN102516343A CN102516343A CN2011103547473A CN201110354747A CN102516343A CN 102516343 A CN102516343 A CN 102516343A CN 2011103547473 A CN2011103547473 A CN 2011103547473A CN 201110354747 A CN201110354747 A CN 201110354747A CN 102516343 A CN102516343 A CN 102516343A
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Abstract
The invention relates to a novel antitumor compound ginsenoside Rh2 derivative and preparation thereof. A preparation method comprises the following steps of: extracting ginseng with a water decoction method, and separating general ginsenoside out by using macroporous resin D101; adding alcohol into the general ginsenoside for fully dissolving, adding strong alkali for separating diol saponin, hydrolyzing and oxidizing C24 into carboxyl by using oxidants (potassium permanganate and sodium acid chromate); and performing column chromatography and thin layer chromatography tracking detection, separating to obtain a ginsenoside Rh2 derivative intermediate, and reacting the intermediate with 40 percent aqueous alkali (including sodium hydrate or potassium hydrate) to generate a salt, i.e., A2, wherein an eluent is a (V/V) lower layer consisting of methanol, ethyl acetate, chloroform and water in the ratio of 5:4:4:1. The structure of ginsenoside Rh2 is chemically modified, so that high water solubility, high bioavailability and high anticancer activity are achieved, and a novel ideal antitumor medicament which is efficient and has low toxicity and a broad spectrum is obtained; and a process is simple and practicable, quality is controllable, high repeatability is achieved, and the method is suitable for mass production.
Description
Technical field
The present invention relates to a kind of new antitumoral compounds ginsenoside Rh
2Verivate and preparation thereof.
Background technology
Genseng is the traditional Chinese medicine of motherland's medical science, has the effect of strengthening the body resistance to consolidate the constitution, and just is regarded as treasure by people since ancient times.In recent years, many researchs show, the ginsenoside Rh
2Has many-sided anti-tumor activity.The latest study proves the ginsenoside Rh through cancer cells vitro culture and animal model for cancer
2Cancer cells such as melanoma, mammary cancer, ovarian cancer, liver cancer, lung cancer, osteocarcinoma, carcinoma of the pancreas, colorectal carcinoma, leukemia are brought into play restraining effect from following several respects: 1. anticancer growth; 2. bring out cancer cell-apoptosis; 3. inducing cancer cell differentiation; 4. enhancing body immunologic function etc.Modern study shows, the ginsenoside Rh
2The independent effective mediator's body immunity function of use, after operation or put, chemotherapeutic period is used, and can effectively protect immune organ, raise immunity helps immunosurveillance and the normal performance of removing function, but preventing cancer recurrence and transfer.Many-sided pharmaceutical research confirms the ginsenoside Rh
2Have low toxicity, wide spectrum and press down the knurl characteristics, cancer cells is reversed be normal cell.Thus it is clear that, the ginsenoside Rh
2Near an optimal cancer therapy drug,, improve its bioavailability, so the ginsenoside Rh if make it water-soluble
2Will become an optimal PTS: efficient, wide spectrum, low toxicity.
Summary of the invention
The object of the present invention is to provide a kind of new antitumoral compounds ginsenoside Rh
2Verivate and preparation thereof, it is with the ginsenoside Rh
2Structure carry out chemically modified, good water solubility, bioavailability are high to reach, antitumour activity is strong, make it become an ideal PTS: efficient, low toxicity, wide spectrum; The present invention is simple for process, and is quality controllable, and favorable reproducibility is suitable for big production.
Technical scheme of the present invention is achieved in that the new antitumoral compounds ginsenoside Rh
2Verivate and preparation thereof is characterized in that: the ginsenoside Rh
2The structural formula of verivate A2 is following,
Structural formula A2:
Chemical name: 24-removes sec.-propyl-12 β .20 (R&S)-dihydroxyl Da Ma-C
24-sour sodium (potassium)-3-oxygen-β-D-glucopyranoside
Molecular formula: C
33H
56O
10Na (K)
Molecular weight: 635.87 (651.87)
The preparation method is following:
Get genseng and adopt decocting method to extract, use macroporous resin D again
101Isolate Radix Ginseng total saponins.After then Radix Ginseng total saponins being added alcohol and dissolves fully, add highly basic glycol saponins is separated,, use oxygenant (potassium permanganate, sodium dichromate 99) oxidation again, make C then with its hydrolysis
24Be oxidized to carboxyl.This thing is carried out column chromatography, and thin layer chromatography is followed the tracks of and is detected, and eluent is a methyl alcohol: ETHYLE ACETATE: chloroform: water=5:4:4:1 (V/V) lower floor, separate obtaining the ginsenoside Rh
2The verivate midbody, alkaline solution (comprising sodium hydroxide or the Pottasium Hydroxide) effect with this thing and 40% generates salt and promptly gets A2.
Positively effect of the present invention is that good water solubility, bioavailability are high, antitumour activity is strong, with the ginsenoside Rh
2Novel derivative A2 carries out soluble test: get the 1.0g ginsenoside Rh
2Novel derivative A2 can be dissolved in the 4ml water fully, makes it become an ideal PTS: efficient, low toxicity, wide spectrum; It is simple for process, and is quality controllable, and favorable reproducibility is suitable for scale operation.
Embodiment
Below in conjunction with embodiment the present invention is done further description,Embodiment is not equal to restriction the present invention for further illustrating characteristics of the present invention,, all should be included within protection scope of the present invention according to the change that the present invention carries out for those skilled in the art.
Embodiment 1: prepare A2 with potassium permanganate oxidation method
Get genseng 100kg, decocting is used macroporous resin adsorption; 80% ethanol elution, the decolouring of yin, yang ion exchange resin gets Radix Ginseng total saponins 3000g; This thing is dissolved among the ethanol 5000-6000ml, stirs the aqueous solution that adding down contains sodium hydroxide 1000-1200g, be heated to 40 ℃; Separate out glycol saponins, filter, get 1800g.This thing is dropped in stainless steel reactor, glycerol adding 18000g, heating, hydro-oxidation sodium 2000-2300g is heated to 180-200 ℃, keeps 20-40 minute, hydrolysis is accomplished, and reaction solution is splashed in the water, separates out deposition, filter, dry, get hydrolyzate 610g.This thing is dissolved in the acetone, adds and contain an amount of aqueous solution of potassium permanganate, 50 ℃ of-60 ℃ of oxidations, filter, remove the Manganse Dioxide of generation, filtrating is reclaimed acetone, gets ginsenoside verivate midbody, the dry dry product 400g that gets.Through column chromatography for separation, thin layer chromatography is followed the tracks of and is detected with this thing, and eluent is a methyl alcohol: ETHYLE ACETATE: chloroform: water=5:4:4:1 (V/V) lower floor.Get pure ginsenoside Rh
2Verivate midbody 92.30g, the sodium hydroxide solution effect generation salt with this thing and 40% promptly gets structural formula A2 compound, must measure to be 96.40g.
Embodiment 2: prepare A2 with the sodium dichromate 99 oxidation style
Press embodiment 1 and prepare the method for hydrolyzate, obtain glycol saponins hydrolyzate 595g, be dissolved in the acetone; Add the aqueous solution that contains sodium dichromate 99 160-200g, get ginsenoside verivate midbody, filter 50 ℃ of-80 ℃ of oxidations; Residue discards, and filtrating is reclaimed acetone, the dry 390g that gets.This thing is carried out column chromatography for separation, and operation gets the ginsenoside Rh with embodiment 1
2Verivate midbody 87.60g with it and 40% sodium hydroxide solution effect, promptly gets A2, must measure to be 92.20g.
Embodiment 3: prepare A2 with potassium permanganate oxidation method
Get genseng 100kg, decocting is used macroporous resin adsorption; 80% ethanol elution, the decolouring of yin, yang ion exchange resin gets Radix Ginseng total saponins 3000g; This thing is dissolved among the ethanol 5000-6000ml, stirs the aqueous solution that adding down contains Pottasium Hydroxide 1000-1200g, be heated to 40 ℃; Separate out glycol saponins, filter, get 1770g.This thing is dropped in stainless steel reactor, glycerol adding 18000g, heating, hydro-oxidation potassium 2000-2300g is heated to 180-200 ℃, keeps 20-40 minute, hydrolysis is accomplished, and reaction solution is splashed in the water, separates out deposition, filter, dry, get hydrolyzate 595g.This thing is dissolved in the acetone, adds and contain an amount of aqueous solution of potassium permanganate, 50 ℃ of-60 ℃ of oxidations, filter, remove the Manganse Dioxide of generation, filtrating is reclaimed acetone, gets ginsenoside verivate midbody, the dry dry product 390g that gets.Through column chromatography for separation, thin layer chromatography is followed the tracks of and is detected with this thing, and eluent is a methyl alcohol: ETHYLE ACETATE: chloroform: water=5:4:4:1 (V/V) lower floor.Get pure ginsenoside Rh
2Verivate midbody 85.80g, the potassium hydroxide solution effect generation salt with this thing and 40% promptly gets structural formula A2 compound, must measure to be 90.50g.
Embodiment 4: prepare A2 with the sodium dichromate 99 oxidation style
Press embodiment 3 and prepare the method for hydrolyzate, obtain glycol saponins hydrolyzate 587g, be dissolved in the acetone; Add the aqueous solution that contains sodium dichromate 99 160-200g, get ginsenoside verivate midbody, filter 50 ℃ of-80 ℃ of oxidations; Residue discards, and filtrating is reclaimed acetone, the dry 376g that gets.This thing is carried out column chromatography for separation, and operation gets the ginsenoside Rh with embodiment 3
2Verivate midbody 83.00g with it and 40% potassium hydroxide solution effect, promptly gets A2, must measure to be 88.03g.
Claims (3)
1. new antitumoral compounds ginsenoside Rh
2Verivate is characterized in that: the ginsenoside Rh
2Verivate A2 is that 24-removes sec.-propyl-12 β .20 (R&S)-dihydroxyl Da Ma-C
24-sour sodium-3-oxygen-β-D-glucopyranoside, its structural formula is following,
Structural formula A2:
Molecular formula: C
33H
56O
10Na (K)
Molecular weight: 635.87 (651.87).
2. new antitumoral compounds ginsenoside Rh according to claim 1
2Verivate is characterized in that described ginsenoside Rh
2Verivate A2 is that 24-removes sec.-propyl-12 β .20 (R&S)-dihydroxyl Da Ma-C
24-sour potassium-3-oxygen-β-D-glucopyranoside.
3. new antitumoral compounds ginsenoside Rh according to claim 1
2Verivate is characterized in that described ginsenoside Rh
2The preparation method of verivate A2 is following: get genseng and adopt decocting method to extract, use macroporous resin D again
101Isolate Radix Ginseng total saponins, after then Radix Ginseng total saponins being added alcohol and dissolves fully, add highly basic glycol saponins is separated,, use oxygenant (potassium permanganate, sodium dichromate 99) oxidation again, make C then with its hydrolysis
24Be oxidized to carboxyl, products therefrom is carried out column chromatography, thin layer chromatography is followed the tracks of and is detected, and eluent is a methyl alcohol: ETHYLE ACETATE: chloroform: water=5:4:4:1 (V/V) lower floor, separate obtaining the ginsenoside Rh
2The verivate midbody, alkaline solution (comprising sodium hydroxide or the Pottasium Hydroxide) effect with this thing and 40% generates salt and promptly gets A2.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004307390A (en) * | 2003-04-07 | 2004-11-04 | Mitsubishi Chemicals Corp | Method for producing steroid compound |
| US20060252948A1 (en) * | 2004-07-13 | 2006-11-09 | Jun Takehara | Production method of steroid compound |
| CN101781353A (en) * | 2010-03-05 | 2010-07-21 | 中南大学 | 20(S)-ginsenoside Rh2 derivatives for regulating and controlling ER Alpha/ER Beta-TNF Alpha channel as well as preparation and anti-tumor application thereof |
| CN101880304A (en) * | 2010-06-21 | 2010-11-10 | 李平亚 | 24(R)-pseudoginsenoside-GQ as well as semisynthesis method and medicinal application thereof |
-
2011
- 2011-11-10 CN CN2011103547473A patent/CN102516343A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004307390A (en) * | 2003-04-07 | 2004-11-04 | Mitsubishi Chemicals Corp | Method for producing steroid compound |
| US20060252948A1 (en) * | 2004-07-13 | 2006-11-09 | Jun Takehara | Production method of steroid compound |
| CN101781353A (en) * | 2010-03-05 | 2010-07-21 | 中南大学 | 20(S)-ginsenoside Rh2 derivatives for regulating and controlling ER Alpha/ER Beta-TNF Alpha channel as well as preparation and anti-tumor application thereof |
| CN101880304A (en) * | 2010-06-21 | 2010-11-10 | 李平亚 | 24(R)-pseudoginsenoside-GQ as well as semisynthesis method and medicinal application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ATOPKINA, LYUBOV N. 等: "Cytotoxicity of natural ginseng glycosides and semisynthetic analogs", 《PLANTA MEDICA》, vol. 65, no. 1, 28 February 1999 (1999-02-28), pages 30 - 34 * |
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Application publication date: 20120627 |