CN101838296B - Preparation method and application of new poly-alkyne-glycoside - Google Patents
Preparation method and application of new poly-alkyne-glycoside Download PDFInfo
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- CN101838296B CN101838296B CN201010169063.1A CN201010169063A CN101838296B CN 101838296 B CN101838296 B CN 101838296B CN 201010169063 A CN201010169063 A CN 201010169063A CN 101838296 B CN101838296 B CN 101838296B
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Abstract
The invention relates to the field of natural medicinal chemistry, in particular to new poly-alkyne-glycoside extracted and separated from a Chinese medicament namely atractylis lancea, and also discloses a preparation method of the new poly-alkyne-glycoside, and application of the poly-alkyne-glycoside in preparing anti-inflammatory medicaments.
Description
One, technical field:
The present invention relates to natural medicine field, be specifically related to extract the new poly-alkyne-glycoside that separation obtains from Chinese medicine Atractylis lancea, its preparation method, and this poly-alkyne-glycoside is in the purposes of preparing in anti-inflammatory drug.
Two, technical background:
Atractylis lancea (Atractylodes lancea (Thunb.) DC.) is composite family (Compositae) Atractylodes (Atractylodes) plant, be one of two kinds of Original plants of 2005 editions contained rhizoma atractylodis medicinal materials of the Pharmacopoeia of the People's Republic of China, another kind is Atractylis chinensis A.lancea (Thunb.) DC var.chinensis (Bunge) Kitam..There is effect of drying damp and strengthening spleen, expelling wind and cold, improving eyesight, at tcm clinical practice and the distension and fullness in the abdomen that is widely used among the people, have loose bowels, poor appetite, oedema, beriberi impotence numbness, common cold caused by wind-cold, the diseases such as night blindness yctalopia.
Atractylodes plant main chemical compositions: volatile oil, glycoside, sugar and polysaccharide etc.Main pharmacologically active have antimicrobial antiphlogistic, antiulcer agent, hypoglycemic, the effect such as protect the liver.The Chinese Academy of Sciences of Jiangsu Province medicinal plants study development centre, in to the separation of Atractylis lancea water soluble component, obtains a new poly-alkyne-glycoside compound, the clear and definite structure of this compound.Pharmaceutical research shows that this compound is inhibited to cyclooxygenase, can be developed as anti-inflammatory drug.
Three, summary of the invention:
The invention provides a kind of new poly-alkyne-glycoside compound (1): triolefin-7 in the last of the ten Heavenly stems, erythro form-(1,3Z, 11E)-13,9-diine-5-hydroxyl-6-O-β-D-glycopyranoside, its structure is as follows
The invention provides the preparation method of above-claimed cpd, it is characterized in that: take the fresh rhizome of Atractylis lancea as raw material, through water or organic reagent or mixed solvent extraction, aqueous extract is directly crossed macroporous resin adsorption, after mixed solvent extracting solution is concentrated, be dissolved in water through macroporous resin adsorption or n-butanol extraction, macroporous resin adsorption thing or n-butyl alcohol extract obtain through column chromatography for separation again.Macroporous resin is D101 type macroporous resin; Column chromatography is selected from one or more in silica gel, ODS or gel SephadexLH-20 with carrier; Organic solvent comprises methyl alcohol, ethanol or propyl carbinol; Extract temperature lower than 100 ℃.
The invention provides compound 1 and form pharmaceutical composition and preparation thereof with medically acceptable pharmaceutical excipient.As, tablet, pill, paste, capsule, oral liquid, granule and injection liquid powder injection or liquid drugs injection liquid.
Four, accompanying drawing explanation:
Can be used as annex material with figure below reports.
Fig. 1 compound 1
1h-NMR spectrum
Fig. 2 compound 1
13c-NMR spectrum
The hsqc spectrum of Fig. 3 compound 1
The HMBC spectrum of Fig. 4 compound 1
Five, embodiment:
In conjunction with embodiment, the invention will be further described, but content of the present invention is not restricted to cited embodiment.
The fresh rhizome 60Kg of Atractylis lancea, with 95% alcohol reflux three times, 200 liters of consumptions, each 10 days, the concentrated concentrated solution being merged into without alcohol taste, obtained total medicinal extract.Use successively again sherwood oil, ethyl acetate and n-butanol extraction.Propyl carbinol portion extract is through D101 macroporous resin adsorption, water, 50% ethanol, 90% ethanol elution.50% ethanol eluate decompression and solvent recovery obtains mixture.Mixture after column chromatography (silica gel column chromatography: chloroform-methanol system, RP-C18 column chromatography: water-methanol system) separates, obtains compound 1 (26.9mg) again.
Embodiment 2 separates and authenticating compound 1 from the fresh rhizome of Atractylis lancea
The fresh rhizome 40Kg of Atractylis lancea, water heating is extracted three times, and water consumption is 20 liters, extraction time is 1 hour, and extracting temperature is 70 ℃, and extracting solution is through D101 macroporous resin adsorption, water, uses 90% ethanol elution after 50% alcohol flushing, 50% ethanol eluate decompression and solvent recovery obtains mixture.Mixture after column chromatography (silica gel column chromatography: chloroform-methanol system, RP-C18 column chromatography: water-methanol system) separates, obtains compound 1 (20.8mg) again.
Embodiment 3 separates and authenticating compound 1 from the fresh rhizome of Atractylis lancea
The fresh rhizome 40Kg of Atractylis lancea, with methyl alcohol cold soaking extraction three times, methanol usage is 20 liters, and extraction time is 7 days, and extracting solution is through D101 macroporous resin adsorption.Water, uses 90% ethanol elution after 50% alcohol flushing, 50% ethanol eluate decompression and solvent recovery obtains mixture.Mixture after column chromatography (silica gel column chromatography: chloroform-methanol system, RP-C18 column chromatography: water-methanol system) separates, obtains compound 1 (22.3mg) again.
The physicochemical data of compound 1
Molecular formula is C
19h
24o
7, high resolution electron spray(ES) positive ion mass spectrum (HRESIMS), m/z[M+Na]
+, [2M+Na]
+: 387.1326,751.3009, specific rotatory power
-43.87 ° (C=0.098, MeOH), proton nmr spectra
1h-NMR (C
5d
5n, 500MH
z): δ ppm 5.20 (br.d, 1H, J=16.8Hz, H-1a), 5.09 (br.d, 1H, J=10.1Hz, H-1b), 6.95 (dddd, 1H, J=16.8, 10.0, 11.0, 1.0Hz, H-2), 6.23 (dd, 1H, J=10.0, 8.7Hz, H-3), 6.09 (dd, 1H, J=10.0, 8.7Hz, H-4), 5.35 (dd, 1H, J=3.5, 8.3Hz, H-5), 5.25 (d, 1H, J=3.5Hz, H-6), 5.50 (dd, 1H, J=1.0, 15.8Hz, H-11), 6.19 (dq, 1H, J=6.9, 15.8Hz, H-12), 1.53 (dd, 3H, J=1.6, 6.9Hz, H-13), 5.38 (d, 1H, J=7.8Hz, H-1 '), 4.06 (m, 1H, H-2 '), 3.96 (m, 1H, H-3 '), 4.24 (m, 1H, H-4 '), 4.21 (m, 1H, H-5 '), 4.35 (dd, 1H, J=5.2, 11.8Hz, H-6 ' a), 4.50 (br d, 1H, J=2.4, 11.8Hz, H-6 ' b),
13c-NMR (C
5d
5n, 125MH
z) spectrum: δ ppm 119.31 (C-1), 133.00 (C-2), 132.03 (C-3), 131.23 (C-4), 70.22 (C-5), 75.03 (C-6), 80.25 (C-7), 72.10 (C-8), 73.00 (C-9), 78.12 (C-10), 109.8 (C-11), 144.8 (C-12), 18.57 (C-13), 104.23 (C-1 '), 75.61 (C-2 '), 78.86 (C-3 '), 71.44 (C-4 '), 78.48 (C-5 '), 62.53 (C-6 ').
Can obtain in conjunction with coherent signal in hsqc spectrum: contain an end group alkene, two disubstituted pair of keys, two tertiary carbons that are connected with oxygen [δ C-5:70.21, δ H-5:5.35, (dd, J:3.5,8.3); δ C-6:75.02, δ H-6:5.25, (br.d, J:3.5)], a methyl and β-Glucopyranose residue.
The aglycon structure of inferring compound 1 in conjunction with coherent signal in hsqc spectrum is triolefin-7 in the last of the ten Heavenly stems, (1,3Z, 11E)-13,9-diine-5,6-glycol.HMBC spectrum shows sugared anomeric proton signal (Glc H-1, δ 5.38, d, J:7.8; Gly C-1: δ 104.23) and δ 75.02 (C-6) distant relation, infer that C-6 is connected with glucose C-1 '.
Therefore the two dimensional structure of compound 1 is triolefin-7 in the last of the ten Heavenly stems, (1,3Z, 11E)-13,9-diine-5,6-glycol 6-O-β-D-glycopyranoside.In all polyethylene alkynes vicinal diol compounds of getting from Atractylis lancea, the absolute configuration of two chiral carbon all cannot be determined.Searching document can obtain, and in the time that the coupling constant of proton on two adjacent adjacent glycol is 4Hz left and right, the relative configuration of compound is erythro form; In the time that the coupling constant of two adjacent protons is 5～8Hz left and right, the relative configuration of compound is Soviet Union's formula.So the structure of compound 1 is triolefin-7 in the last of the ten Heavenly stems, erythro form-(1,3Z, 11E)-13,9-diine-5-hydroxyl-6-O-β-D-glycopyranoside.
The cyclooxygenase of embodiment 4. compounds 1 suppresses activity research
1, material
Poly-alkyne-glycoside: triolefin-7 in the last of the ten Heavenly stems, (1,3Z, 11E)-13,9-diine-5-hydroxyl-6-O-β-D-glycopyranoside
Healthy human blood; Heparin sodium (packing factory of Solution on Chemical Reagents in Shanghai company, 890525); Lipopolysaccharides (LPS, SIGMA, L-2880); TXB
2radioimmunological kit (Kemei Dongya Biological Technology Co., Ltd., Beijing); 6-ketone-PGF1α (6-keto-PGF1 α) radioimmunological kit (English biotechnology research institute of Beijing China); Celecoxib (Celecoxib capsules, the large pharmaceutical factory of Xi Er Bo Duoli subsidiary factory); Asprin enteric coated tablet (Nanjing Hencer Pharmaceutical Factory, 040303)
Use instrument model: DFM-98 type 16 pipe radioimmunity γ registers
2, method and result
Adopt people's whole blood method, get healthy human blood, be placed in the test tube that contains heparin sodium aqua (19 units per ml), mix, get 96 well culture plates, every hole adds whole blood 100 μ l.
The inhibition experiment of COX-1: medicine dissolves with 0.1%DMSO respectively, adds respectively the medicine of different concns in whole blood, 50 μ l/well, making final concentration is 10
-3, 10
-4, 10
-5m, blank group adds PBS (0.1%DMSO), and 50 μ l/well add aspirin in positive group, 50 μ l/well, making final concentration is 10
-3m.In 37 ℃, 5%CO
2in incubator, cultivate after 60min, take out, add calcium ion carrier A 23187 (50 μ M, except blank group).37 ℃, 5%CO
2in incubator, cultivate 30min.Take out, centrifugal culture plate (2000rpm, 4 ℃, 5min), draws supernatant liquor freezing in-20 ℃ immediately.Press radioimmunological kit method and survey TXB in supernatant liquor
2content.The results are shown in Table 1.
The inhibition experiment of COX-2: every hole first adds 50 μ l aspirin (72 μ g/ml), 37 ℃, 5%CO
2in incubator, cultivate 6h, deactivation COX-1.Then add lipopolysaccharide (LPS, 30 μ g/ml) 20 μ l/well, the medicine of different concns, 50 μ l/well, making final concentration is 10
-3, 10
-4, 10
-5m, blank group adds PBS (0.1%DMSO), and 50 μ l/well add celecoxib in positive group, 50 μ l/well, making final concentration is 10
-4m.37 ℃, 5%CO
2in incubator, cultivate 18h.Take out, centrifugal culture plate (2000rpm, 4 ℃, 5min), draws supernatant liquor freezing in-20 ℃ immediately.Press the content that radioimmunological kit method is surveyed 6-ketone-PGF1α (6-keto-PGF1 α) in supernatant liquor.The results are shown in Table 2.
The inhibition experimental result of table 1. poly-alkyne-glycoside to COX-1
The inhibition experimental result of table 2. poly-alkyne-glycoside to COX-2
Adopt generally acknowledged people's whole blood external test method, evaluate drug effect effect of COX-2 system in COX-1 system and white corpuscle in thrombocyte, result shows that this poly-alkyne-glycoside is to stimulating thromboxane (TXB in the blood causing because of calcium ion carrier A 23187
2) raising has weak inhibition, the rising that LPS is stimulated to 6-ketone-PGF1α in the blood causing (6-keto-PGF1 α), has obvious restraining effect.Indirectly show that this poly-alkyne-glycoside has weak inhibition to COX-1, has good restraining effect to COX-2.TXB
2that arachidonic acid (AA) changes into PG class material (wherein PGE through COX
2important inflammation-causing substance) by product, produced by COX-1 in thrombocyte, can induced platelet assemble, vasoconstriction also promotes blood vessel hyperplasia, assists inflammation to occur.6-ketone-PGF1α (6-keto-PGF1 α) is also the product through COX effect in addition, is produced by the COX-2 of blood vessel endothelium, can anticoagulant, and vasodilator also suppresses vascular endothelial proliferation.Measure thromboxane (TXB in whole blood
2), the content of 6-ketone-PGF1α (6-keto-PGF1 α) can reflect the activity of COX indirectly.
The impact of embodiment 5. on Mice Auricle dimethylbenzene inflammation
To 60 random point 5 groups of male mices, 1. 2. poly-alkyne-glycoside I (10mgkg of model group
-1), poly-alkyne-glycoside II (20mgkg
-1), poly-alkyne-glycoside III (40mgkg
-1) three 3. indomethacin group (8mgkg of dosage group
-1), give each group of gastric infusion or give the physiological saline of equivalent, every day 1 time, for three days on end, 30min after last administration, outside in every mouse auris dextra exterior feature, drip and be coated with 20 μ l caused by dimethylbenzene xylene inflammation, in contrast, the de-cervical vertebra of extremely scorching rear 30min is put to death mouse to left ear, lay auricle respectively at left and right ear same area with diameter 7mm punch tool, weigh, represent swelling with left and right auricle difference, the results are shown in Table 3.
Table 3. poly-alkyne-glycoside p-Xylol induced mice auricle inflammation is swollen
impact (± S, n=12)
With model group comparison
*p < 0.05,
*p < 0.01
Experimental result shows, this poly-alkyne-glycoside 20mgkg
-1and 40mgkg
-1two dosage group p-Xylol induced mice ear swellings have obvious restraining effect, point out this poly-alkyne-glycoside to have certain anti-inflammatory action, can be used for the exploitation of anti-inflammatory drug.
Embodiment 6. is containing the tablet of new poly-alkyne-glycoside monomer of the present invention
Get new poly-alkyne-glycoside 20mg and starch 80mg that embodiment 1 makes, dextrin 50mg, Icing Sugar 45mg mixes, and makes softwood, and ordinary method is granulated, and adds appropriate Magnesium Stearate to mix, and makes tablet.
Embodiment 7. is containing the capsule of new poly-alkyne-glycoside of the present invention
Get new poly-alkyne-glycoside monomer 20mg and starch 28mg, dextrin 10mg mixes, and makes softwood, and ordinary method is granulated, and packs in hard capsule.
Claims (5)
1. a poly-alkyne-glycoside compounds for formula (I), chemical name is: triolefin-7 in the last of the ten Heavenly stems, erythro form-(1,3Z, 11E)-13,9-diine-5-hydroxyl-6-O-β-D-glycopyranoside, chemical structure is as follows:
2. the preparation method of compound claimed in claim 1, it is characterized in that fresh rhizome take composite family (Compositae) Atractylodes (Atractylodes) plant Atractylis lancea (Atractylodes lancea (Thunb.) DC.) is as raw material, through water or organic solvent or mixed solvent extraction, aqueous extract is directly crossed macroporous resin adsorption, after organic solvent or mixed solvent extracting solution are concentrated, be dissolved in water through macroporous resin adsorption or n-butanol extraction, macroporous resin adsorption thing or n-butyl alcohol extract obtain through column chromatography for separation again;
Wherein, macroporous resin is D101 type macroporous resin; Column chromatography is selected from one or more in silica gel, ODS or gel Sephadex LH-20 with carrier; Organic solvent is selected from methyl alcohol, ethanol or propyl carbinol; Extract temperature lower than 100 ℃.
3. a pharmaceutical preparation, it is made up of compound claimed in claim 1 and medically acceptable pharmaceutical excipient.
4. pharmaceutical preparation claimed in claim 3, is characterized in that preparation formulation is tablet, capsule, granule, oral liquid or injection.
5. compound claimed in claim 1 is in the purposes of preparing in anti-inflammatory drug.
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Non-Patent Citations (2)
| Title |
|---|
| Further Phenols and Polyacetylenes from the Rhizomes of Atractylodes lancea and their Anti-Inflammatory Activity;M.Resch et al.;《Planta Med.》;20011231;第67卷;437-442 * |
| M.Resch et al..Further Phenols and Polyacetylenes from the Rhizomes of Atractylodes lancea and their Anti-Inflammatory Activity.《Planta Med.》.2001,第67卷437-442. |
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