CN1238333C - Medicinal compound pineapple acyl ester, preparation method and use thereof - Google Patents
Medicinal compound pineapple acyl ester, preparation method and use thereof Download PDFInfo
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- 235000007119 Ananas comosus Nutrition 0.000 title claims abstract description 72
- -1 acyl ester Chemical class 0.000 title claims abstract description 45
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- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pineapple acyl ester medicinal compound, a preparation method thereof, and a usage thereof, particularly a new medicinal compound extracted from pineapple leaves and a preparation method thereof. The medicinal compound has a structural formula (I). The present invention also relates to an application of the medicinal compound for preparing medicine for treating diseases resulting from peroxide raising in bodies, low-density of oxidization or high-density lipoprotein raising.
Description
Technical field
The present invention relates to a kind of new medical compounds pineapple acyl ester, preparation method and the new purposes aspect medical thereof, belong to technical field of traditional Chinese medicines.
Pineapple is bromelia pineapple Ananas comosus (L.) Merr.[Bromelia comosa L.; A.sativusSchult.Et Schult.f.] fruit.Originate in America, existing extensively planting in the torrid areas, all there is plantation on ground such as China Fujian, Guangdong, Hainan, Guangxi, Yunnan.This product beginning is stated from clearly. and Wu Qirui " An Illustrated Book on Plants ", run after fame to reveal pocket.This secretary is carried: " reveal pocket and produce Guangdong, a POLO is given birth between hill, and is real in radish, the acropetal leaf cluster, and the long dark tooth of point, flavor look fragrant tool is good.The ripe golden yellow of fruit, Pi Jian such as fish scale shape, peeling food meat, fragrant and sweet no slag, June is ripe ".
Ancient times does not have clearly record for pineapple leaves, the raw material that modern people arghan commonly used is braiding and papermaking (" the Chinese Higher plant illustrated handbook. the 5th " Science Press 1976).Pineapple leaves on the books has and helps digestion and stomach when near, and the antidiarrheic effect cures mainly summer heat and rushes down, maldigestion, gastral cavilty distending pain etc. (" China's book on Chinese herbal medicine. the 8th volume " Shanghai science tech publishing house 1999).
Pineapple leaves is more rare as medicinal record, the new compound-pineapple acyl ester of from the pineapple leaves separation and Extraction of especially not appearing in the newspapers and the new purposes aspect medical thereof.
Summary of the invention
The purpose of this invention is to provide a kind of new medical compounds pineapple acyl ester.
Another object of the present invention provides a kind of preparation method of pineapple acyl ester.
A further object of the present invention provides the purposes of pineapple acyl ester aspect medical.
Medical compounds pineapple acyl ester provided by the invention, shown in its chemical structural formula (I):
Pineapple acyl ester specifically provided by the invention is a kind of new compound that separates preparation from pineapple leaves, systematic naming method is 1,3-O-di[β-(3,4-dihydroxyphenyl) propenoyl] glycerides, Chinese name, 1,3-O-two-β-3,4-two-hydroxy phenyl acryloyl glyceryl ester, its structure are as shown in the formula (II):
The physico-chemical property and the various wave spectrum feature thereof of described new compound pineapple acyl ester are as follows:
This compound is faint yellow amorphous solid, mp 210-216 ℃, and FeCl
3Show black-and-blue, be soluble in organic solvents such as acetone, methyl alcohol and ethanol.
UVλmax(MeOH)nm：219，244，326。
IRνmax(KBr)cm
-1：3386，1683，1638，1601，1532，1446，1375，1284，1184，1112，976，811，596。
HRFAB-MS:415.1034[M-1]
-, (calculated value is 415.1034, and molecular formula is C
21H
20O
9)
Nucleus magnetic resonance
1HNMR,
13CNMR and DEPT data such as following table:
Nmr spectrum data (the acetone-d of pineapple acyl ester
6, δ ppm)
| NO. | 13C-NMR | DEPT | 1H-NMR |
| 1 2 3 >＝0 α，α′ β，β′ 1′，1″ 2′，2″ 3′，3″ 4′，4″ 5′，5″ 6′，6″ OH | 65.09 67.47 65.09 166.43 114.35 145.12 126.70 114.49 145.41 147.91 115.48 121.66 | CH 2 CH CH 2 CH CH CH CH CH | 4.26(2H，m) 4.17(1H，m) 4.26(2H，m) 6.31(2H，d，J＝16Hz) 7.60(2H，d，J＝16Hz) 7.16(2H，d，J＝2.0Hz) 6.86(2H，d，J＝8.0Hz) 7.04(2H，dd，J＝2.0，8.0Hz) 8.32(4H，s) |
The present invention also provides a kind of preparation method of above-mentioned pineapple acyl ester, and this method comprises the steps:
(1) elder generation carries out routine heating extraction with 5～10 times alcoholic solvent of medicinal material weight with pineapple leaves, obtains extracting solution;
(2) with extracting solution behind concentrating under reduced pressure under 50～90 ℃ of temperature, with 2～5 times of water dissolution of medicinal material weight, centrifugal or static filtration discards precipitation, gets supernatant liquor;
(3) supernatant liquor is passed through macroporous adsorbent resin, first water wash-out, elutriant is discarded, uses concentration greater than 70% ethanol elution again, and at 50～90 ℃ of following concentrating under reduced pressure of temperature, drying under reduced pressure or lyophilize then obtains the pineapple leaves extract with elutriant;
(4) with pineapple leaves extract Diluted Alcohol dissolution with solvents, recycle silicon glue is mixed sample, separates with silica gel column chromatography, uses chloroform: methyl alcohol or sherwood oil: acetone or chloroform: the acetone gradient elution, use the dextrane gel purifying, and promptly make compound pineapple acyl ester.
In above-mentioned preparation method, the Heating temperature that the routine described in the step (1) adds thermal extraction method is 50 ℃～90 ℃, and extraction time is 3 times, is 30 minutes to 2 hours at every turn; It is ethanol, methyl alcohol, propyl alcohol or butanols that used alcoholic solution is extracted in heating, and its concentration is greater than 30%.
Alcohol concn during the pineapple leaves extract is dissolved with Diluted Alcohol solution described in the method for the present invention is 50～70%.
The purposes of new medical compounds pineapple acyl ester provided by the present invention, mainly be meant preparation treatment body endoperoxide raise and the medicine of the disease that causes thus in application and the application in the medicine that preparation treatment vivo oxidation type low-density lipoprotein and high-density lipoprotein (HDL) raise.In particular, this medical compounds is in damage in learning and memory, dementia, atherosclerosis, coronary heart disease and angina pectoris, the application in the diseases such as cerebral thrombosis.
When clinical application,, use separately or prepare the medicine of operable various different dosage forms clinically with other drug with the preparation process of routine.As powder, pill, capsule, tablet, microcapsule, soft capsule, film, suppository, injection, paste, tincture, powder, electuary, aerosol, various external preparations etc.
Experimental result of the present invention shows that pineapple acyl ester has the effect that obvious suppression brain superoxide MDA raises.Treated in vitro, minimum effectively final concentration is 3 * 10
-6G/ml, along with the increase of concentration, restraining effect strengthens.Treated in vitro, the obviously generation of inhibited oxidation type low-density lipoprotein, effective concentration is 0.3-30ug/ml.Pharmacological evaluation shows, pineapple acyl ester has effect anti-oxidant and that inhibited oxidation type low-density lipoprotein raises, with this compound is activeconstituents, can be used for preparing treatment body endoperoxide rising institute and cause illness, and low-density lipoprotein raises caused diseases related, as disorders of lipid metabolism, atherosclerosis, coronary heart disease, dementia, damage in learning and memory, cerebral thrombosis etc.
Embodiment
The following examples and drug study data are confirmed preparation of the said pineapple acyl of the present invention ester and uses thereof, should not regard the following example as limitation of the present invention again simultaneously.
The preparation EXAMPLE l:
At first use 5 times 100% methyl alcohol of medicinal material (500 gram) weight that pineapple leaves is extracted 3 times 50 ℃ of heating, be 30 minutes at every turn.Then with extracting solution after decompression (pressure 98Kpa) concentrates under 50 ℃ of temperature, centrifugal with 2 times of water dissolution of medicinal material weight, discard precipitation; Supernatant liquor is by macroporous adsorbent resin, first water wash-out, elutriant is discarded, uses 95% ethanol elution again, elutriant under 50 ℃ of temperature, reduce pressure (pressure 98Kpa) concentrate, enriched material (pressure 98Kpa) drying that reduces pressure obtains the pineapple leaves extract.Pineapple leaves extract 80% dissolve with ethanol is used 200～300 order silica gel mixed samples again, separates with silica gel column chromatography, sherwood oil: acetone gradient elution, use the dextrane gel purifying, obtain this compound at last---pineapple acyl ester, per kilogram medicinal material can obtain about 40mg pineapple acyl ester.
Preparation embodiment 2:
At first use 10 times 30% ethanol of medicinal material (500 gram) weight that pineapple leaves is extracted 3 times 90 ℃ of heating, be 2 hours at every turn.Extracting solution is in decompression (pressure 98Kpa) then, temperature 90 ℃ concentrate after, with 5 times of water dissolution of medicinal material weight, centrifugal, discard precipitation, supernatant liquor passes through macroporous adsorbent resin, first water wash-out, and elutriant is discarded, use 70% ethanol elution again, elutriant is 90 ℃ of (pressure 98Kpa) concentrating under reduced pressure in temperature, and enriched material decompression (pressure 98Kpa) drying obtains the pineapple leaves extract.Pineapple leaves extract 60% dissolve with ethanol is used 60-80 order silica gel mixed sample again, separates with silica gel column chromatography, use chloroform: the methyl alcohol gradient elution, use the dextrane gel purifying, obtain this compound at last---pineapple acyl ester, per kilogram medicinal material can obtain about 10mg pineapple acyl ester.
The preparation embodiment 3: the extraction of pineapple acyl ester with separate preparation
At first use 10 times 70% ethanol of medicinal material (500 gram) weight that pineapple leaves is extracted 3 times 80 ℃ of heating, be 1 hour at every turn.Extracting solution is in decompression (pressure 98Kpa) then, temperature 50 ℃ concentrate after, with 5 times of water dissolution of medicinal material weight, centrifugal, discard precipitation, supernatant liquor passes through macroporous adsorbent resin, first water wash-out, and elutriant is discarded, use 80% ethanol elution again, elutriant is 50 ℃ of (pressure 98Kpa) concentrating under reduced pressure in temperature, and enriched material decompression (pressure 98Kpa) drying obtains the pineapple leaves extract.Pineapple leaves extract 30% dissolve with ethanol is used 100-200 order silica gel mixed sample again, separates with silica gel column chromatography, use chloroform: the acetone gradient elution, use the dextrane gel purifying, obtain this compound at last---pineapple acyl ester, per kilogram medicinal material can obtain about 50mg pineapple acyl ester.
Effect experiment example 1: to the influence of brain MDA generation
Observe the restraining effect that pineapple leaves extract of the present invention generates mouse brain MDA.The used pineapple acyl of the present invention ester, lot number: 030228.Pineapple acyl ester is mixed with desired concn with physiological saline.Testing used animal is male ICR mouse, non-inbred lines closed colony, and Beijing dimension tonneau China Experimental Animal Center provides, and body weight is 18-22g.Laboratory room temperature 20-22 ℃, relative humidity 40%～60%, the ventilator ventilation, lamp 12h/ day, raise in cages, 10 in every cage, per three days cleaning cage houses are once.
Get normal mouse, get brain after the execution, add physiological saline do homogenate (with the brain ratio be 5: 1).4 ℃ of refrigerators left standstill 5 minutes, got the even muddy liquid in top.Every pipe adds cerebral tissue liquid 150uL, adds different concns soup 50ul, and 37 ℃ of water-baths were hatched 30 fens.Add 10%SDS 0.1ml successively, 50% Glacial acetic acid thiobarbituricacid liquid 0.5ml and 1% hydrochloric acid solution 2ml.Boiling water bath 15 minutes takes out back cold water and put 10 minutes, and 1500 left the heart 15 minutes, gets supernatant and surveys the absorbance A value in the 532nm place.Do three multiple pipes for every group.Calculate inhibiting rate=[(control group A-administration group A)/control group A * 100%].
The gained data are through the EXCEL software processes.T check between group.
This test pineapple acyl ester administration final concentration is respectively 3 * 10
-7G/ml, 3 * 10
-6G/ml, 3 * 10
-5G/ml, 3 * 10
-4G/ml, 3 * 10
-3G/ml.
This test is an experiment in vitro.This test blank is an equal-volume physiological saline. the positive drug contrast is for vitamin-E, available from Sigma company.The experiment final concentration is 3 * 10
-4G/ml.This testing data is all with the Excel software processes.
The external restraining effect that brain MDA is generated of table 2 pineapple acyl ester (x ± s)
| Grouping | Medicine final concentration (g/ml) | Light absorption value (532nm) |
| Physiological saline pineapple acyl ester | 3×10 -3 | 0.236±0.003 0.07±0.003** |
| Pineapple acyl ester pineapple acyl ester pineapple acyl ester pineapple acyl ester vitamins C | 3×10 -4 3×10 -5 3×10 -6 3×10 -7 3×10 -4 | 0.074±0.002** 0.102±0.004** 0.161±0.004** 0.202±0.003* 0.146±0.0011** |
Compare * P＜0.05, * * P＜0.01 with the physiological saline group.n＝3
This experimental result shows, the external effect that has inhibition strongly to lack sugared anoxic cerebral tissue MDA generation of pineapple acyl ester, and minimal effective concentration is 3 * 10
-6G/ml.Prompting pineapple acyl ester has certain oxidation resistant effect, and because of the brain endoperoxide caused neural moral function obstacle that raises, dementia etc. all have positive meaning for control.
Effect experiment example 2: the external restraining effect that the low lipoprotein liter of oxidized form is become
The used male rabbit of the present invention, body weight 2.274 ± 0.537Kg.Animal housing provides by Fu Wai Hospital, Chinese Academy of Medical Sciences.Conformity certification number: No. the 006th, capital moving pipe matter word (96).The used pineapple acyl of the present invention ester, lot number: 030228.Pineapple acyl ester is mixed with desired concn with physiological saline.
The present invention tests the extraction preparation of LDL.Anticoagulant heparin in 25% the urethane auricular vein anesthesia (2ml-4ml/kg), ear vein body, arteria carotis communis is got about blood 100ml, is that the EDTA of 0.4mg/ml is anti-oxidant with final concentration.The centrifugal 10min of 1500rpm gets blood plasma.
Join density gradient liquid:
D=1.0 i.e. the preparation of 0 liquid: 0.01%EDTA, PH=7.4-8.0
The preparation of d=1.1 liquid: get 0 liquid 100mL+NaBr 13.5g
The preparation of d=1.2 liquid: get 0 liquid 100mL+NaBr29.5g
0 liquid 100mL+NaBr 30g is got in the preparation of d=1.21 liquid
The preparation of d=1.3 liquid: get blood plasma 100mL+NaBr 40g
Shop gradient density layer: draw the Beckman centrifuge tube bottom that the 0 liquid 7mL capacity of being laid on is 25.9mL with long syringe needle tube earlier, the d=1.1 liquid minute hand head that then carefully will draw about 7mL inserts Beckman test tube bottom and slowly adds liquid, make 0 liquid come-up, remaining method according to this adds the blood plasma of d=1.3 liquid, and attention must make each liquid level layering.
Ultracentrifugation: angle rotary head Ti50.2, XL-90Beckman centrifuge tube 25.9mL, 45000rpm, 1.4h, 10 ℃.
Dialysis:
The processing of dialysis tubing.With 2% (W/V) NaHCO
3+ 1mmoL/LEDTA (PH8.0) 1000mL boils and (claimed 2gNaHCO in 10 minutes
3Be dissolved among the 100mLD.W., claim 0.37gEDTA to be dissolved among the 1000mLD.W. and get final product).Heavy D.W. washes with 1mmoL/LEDTA (PH8.0) and boiled 10 minutes.Be chilled to 4 ℃ standby.Wash inwall with preceding with heavy D.W..Dialyzate preparation: 0.85%NaCl 8.5g, 0.02Mtris-HCl 2.42g, 0.01%EDTA 0.1g, 0.03%NaN30.3g, 1000mL (pH7.4) altogether.
The dialysis condition: lucifuge, airtight, 4 ℃, 24h changes the 4-5 not good liquor.
PEG-20000 is covered on the dialysis tubing, observes the situation of concentrating (about general simmer down to 1mg/mL) at any time.
Protein quantification.Surveying protein concentration among the LDL in the UV-280nm place, is standard substance with the bovine serum albumin of 1.0mg/mL.
The LDL dilution.The LDL protein concentration is diluted to 0.25mg/mL, 2mL.Time spent 2 times of dilutions, i.e. protein concentration 0.125mg/mL.Each dosage is done 3 multiple pipes.
The LDL test.Get the interior testing drug that adds of liquid of the LDL of 0.125mg/mL, survey the OD value immediately, water-bath then (20 ℃) added CuSO after 30 minutes
4H
2O 5umoL/L, water-bath was measured OD after 30 minutes
234nm. to add CuSO
4H
230 minutes OD value and adding CuSO behind the O
4H
2Difference [the OD of the OD value of surveying before the O
(30 minutes)-OD
(0 minute)], show the speed that its oxidized low-density lipoprotein generates, react the restraining effect of medicine with this.
The used distilled water of the present invention is blank.Positive control drug is vitamins C (analytical pure), lot number: 011206.Beijing fragrant grass pharmaceutical ﹠ chemicall research development corporation produces.
This experimental result is as table 3:
The influence that table 3 different pharmaceutical generates the oxidation low-density lipoprotein
| Dosage (ug/ml) | OD (30 minutes)-OD (0 minute) | |
| Physiological saline model+physiological saline model+pineapple acyl ester model+pineapple acyl ester model+pineapple acyl ester model+vitamins C | 0.3 3 30 0.5 | 0.0073±0.0015 0.0847±0.0161## 0.039±0.0164* 0.0163±0.0068** 0.017±0.003** 0.0203±0.0108** |
Compare ##P＜0.01 with the physiological saline group.Compare * P＜0.05, * * P＜0.01 with model+physiological saline group.n＝3。
Pineapple acyl ester is 0.3,3 at final concentration, during 30ug/ml, to Cu
2SO
4Inductive LDL is oxidized to oxidized ldl (ox-LDL) the obvious suppression effect.Positive control drug VC has the effect that obvious suppression ox-LDL produces.Known ox-LDL has tangible erosion action for arterial smooth muscle, and it can make endotheliocyte impaired, thereby makes blood vessel impaired, and makes thrombosis and attached wall.Therefore the effect of this inhibition ox-LDL of pineapple acyl ester is for preventing that coronary heart disease and cerebral thrombosis have the important clinical meaning.
Claims (7)
1. medical compounds pineapple acyl ester, its chemical structural formula is shown in (I):
2. preparation method of medical compounds pineapple acyl ester according to claim 1, this method comprises the steps:
(1) elder generation heats extraction with pineapple leaves with 5～10 times alcoholic solvent of medicinal material weight under 50 ℃～90 ℃, obtains extracting solution;
(2) with extracting solution behind concentrating under reduced pressure under 50～90 ℃ of temperature, with 2～5 times of water dissolution of medicinal material weight, centrifugal or static filtration discards precipitation, gets supernatant liquor;
(3) with supernatant liquor by macroporous adsorbent resin, first water wash-out, elutriant is discarded, uses concentration greater than 70% ethanol elution again, at 50～90 ℃ of following concentrating under reduced pressure of temperature, drying under reduced pressure or lyophilize then obtains the pineapple leaves extract with elutriant;
(4) with pineapple leaves extract Diluted Alcohol dissolution with solvents, recycle silicon glue is mixed sample, separates with silica gel column chromatography, uses chloroform: methyl alcohol or sherwood oil: acetone or chloroform: the acetone gradient elution, use the dextrane gel purifying, and promptly make compound pineapple acyl ester.
3. according to the preparation method of the described pineapple acyl of claim 2 ester, it is characterized in that: it is ethanol, methyl alcohol, propyl alcohol or butanols that used alcoholic solution is extracted in the heating described in the step (1), and its concentration is greater than 30%.
4. according to the preparation method of the described pineapple acyl of claim 2 ester, it is characterized in that: the extraction time described in the step (1) is 3 times, is 30 minutes to 2 hours at every turn.
5. according to the preparation method of the described pineapple acyl of claim 2 ester, it is characterized in that: the concentration of the Diluted Alcohol described in the step (4) is 50～70%.
6. the application of the described pineapple acyl of claim 1 ester in the medicine of the disease for preparing the endoperoxide rising of treatment body and cause thus.
7. the application of the described pineapple acyl of claim 1 ester in the medicine of preparation treatment vivo oxidation type low-density lipoprotein and high-density lipoprotein (HDL) rising.
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