CN103242416B - Seco-friedelolactone triterpenoid and preparation method as well as application thereof - Google Patents
Seco-friedelolactone triterpenoid and preparation method as well as application thereof Download PDFInfo
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Abstract
The invention relates to a 3,4-seco-friedelolactone triterpenoid. The molecular structure of the compound is shown in the formula (I) in the specification. The compound is obtained by carrying out ethanol reflux extraction, organic solvent extraction and column chromatography separation and purification on viola diffusa ging. The compound has anti-HBV (hepatitis B virus) activity and can be used for preparing medicines for preventing and treating hepatitis B.
Description
Technical field
The present invention relates to Oxygenic heterocyclic compounds, be specifically related to 3,4-driffractive ring friedelane type triterpene compound.
Background technology
Driffractive ring friedelane compounds is few in distributed in nature, nineteen sixty-eight is separated and obtains first 3 from the leaf of Calophyllum Calophyllum apetalum, 4 rupture and become the driffractive ring friedelane compounds apetalactone(Govindachari TR of lactone, Prakash D, Viswanathan N.Apetalactone, a New Triterpene Lactone fromCalophyllum Species.J Chem Soc (C), 1968,1323-1324).Also be separated from congener Calophyllumtomentosum, Calophyllum moonii subsequently and obtain this compound (Dharmaratne HRW; Sotheeswaran S; Balasubramaniam S.Triterpenes and Neoflavonoids of Calophyllum Lankaensis and CalophyllumThwaitesii.Phytochemistry; 1984,23 (11): 2601-2603; Bandara BMR, Dharmaratne HRW, Sotheeswaran S, Balasubramaniam S.Phytochemistry, 1986,25 (2): 425-428).Another driffractive ring friedelane compounds lithocarpic lactone in 1975 is separated and obtains (Hui WH from Lithocarpus zitchioides and the leaf of Lithocarpus irwinii, Li MM, Lee YC.Structure of Lithocarpic Lactone, a New Triterpenoid from TwoLithocarpus Species of Hong Kong.J Chem Soc (Perkin I), 1975:617-619).Within 2009, be separated from the bark of Itoaorientalis and withe and obtain another new driffractive ring friedelane compounds Itoaic acid, and find that this compound has good inhibit activities (Chai XY to COX-2, Xu ZR, Bai CC, Zhou FR, Tu PF.A NewSeco-friedelolactone Acid from the Bark and Twigs of Itoa orientalis.Fitoterapia, 2009,80:408-410).Research group is had to carry out bioactive guided isolation to Calophyllum flavoramulu recently, therefrom also isolate apetalactone, and suppress the activity of AGEs to carry out evaluating (Ferchichi L to it, Derbre S, MahmoodK, Toure K, Guilet D, Litaudon M, Awang K, Hadi AHA, Ray AML, Richomme P.BioguidedFractionation and Isolation of Natural Inhibitors of Advanced Glycation End-products (AGEs) fromCalophyllum flavoramulu.Phytochemistry, 2012, 78:98-106).In sum, the relevant bioactive report of driffractive ring friedelane compounds is few at present, only has the research report suppressing COX-2 and AGEs activity about such compound.
Herba Violae Diffusae (Viola diffusa Ging) is for Violaceae (Violaceae) Viola (Viola) is annual or per nnial herb, have another name called seven-star lotus, viola diffusa etc., be distributed in each province on the south the Changjiang river, district and Shaanxi, Gansu, various places, Fujian are common.Be born in roadside, field, spacious ground or roadside, hillside, also see the moistening place of opening more.All herbal medicine, has clearing heat and detoxicating, dissipating blood stasis for subsidence of swelling, removes necrosis and promote granulation, the effect of removing heat from the lung to relieve cough, and fresh goods mashes external application or dry product levigation damping external application (" Flora Fujian " (Volume Four).Foochow: Fujian science tech publishing house, nineteen ninety).Micro-hardship, cool; There is clearing heat and detoxicating effect.Cure mainly hepatitis, pleuritis, binding film inflammation, venomous snake bite, malignant boil, carbuncle.(" Fujian medicine will " (volume Two. revised edition).Foochow: Fujian science tech publishing house, 1994).
About the chemical research report of this plant is little, records chemical composition contained by this plant according to " Chinese Plants will " and be mainly flavones, carbohydrate and phlegmatic temperament (" Chinese Plants will ".Beijing: Science Press, 1991).To be separated from Herba Violae Diffusae at present and the compound identified has (the Peng Yuangui such as paulownia sterol (clersterol), palmitinic acid (palmitic acid), Zhao Zhenping, Wang Xiaoshu. the effective constituent of Herba Violae Diffusae (hundred grass) leukocyte increasing. herbal medicine, 1990,9:426).Author Hu Dan and Ding Xuliang in 1987 " bulletin of Chinese materia medica " the 12nd volume the 06th phase reported isolated a kind of 3-suberone in violet (Viola verecunda), and carry out finishing structure qualification.Subsequently, He Lan etc. report suberone have anti-inflammatory activity and Antifungi growth effect (He Lan etc. suberone modifying for chemical structure and anti-inflammatory activity thereof. applied chemistry, 1996,13 (5): 67).
Summary of the invention
The technical problem to be solved in the present invention provides a kind of 3,4-driffractive ring friedelane type triterpene compound, and this compound has the effect of anti-treatment hepatitis B virus.
The technical scheme that the present invention will solve the problem is:
A kind of 3,4-driffractive ring friedelane type triterpene compound, its molecular structure is such as formula shown in I:
The molecular formula of 3,4-driffractive ring friedelane type triterpene compounds of the present invention is C
30h
48o
6, HR-ESI-MS m/z503.3393 [M]
-, chemistry 2 β by name, 28 beta-dihydroxyies-3,4-split friedelane-27-carboxylic acid, English 2 β by name, 28 β-dihydroxy-3,4-seco-friedelolactone-27-oic acid.
3,4-driffractive ring friedelane type triterpene compounds of the present invention can by the method for chemosynthesis.Those skilled in the art can by the knowledge determination synthesis step of this area and processing condition.3,4-driffractive ring friedelane type triterpene compounds of the present invention can also be separated and obtain from Herba Violae Diffusae (Viola diffusa Ging), and concrete separation method is made up of lower step:
(1) get Herba Violae Diffusae, (namely the volume of ethanol is the multiple of Herba Violae Diffusae weight to use 12,10 and 8 times successively.If described volume unit is L, described weight unit is kg; If described volume unit is ml, described weight unit to be then concentration g) be 95% alcohol reflux Herba Violae Diffusae herb 2h, merge ethanol extract, reclaim ethanol and be also evaporated to without alcohol taste, obtain total medicinal extract;
(2) total medicinal extract is dissolved in the water, then, uses sherwood oil, vinyl acetic monomer and water saturated n-butanol extraction successively, get butanol extraction liquid, concentrating under reduced pressure, except desolventizing, obtain n-butyl alcohol extract;
(3) n-butyl alcohol extract is dissolved in water, crosses D-101 type macroporous resin column, successively with ethanol, concentration that water, concentration are 10% ethanol that is 30%, the concentration ethanol that is 60%, concentration be 90% ethanol and concentration be the ethanol elution of 95%; Collect concentration be 90% ethanol eluate cross 200 ~ 300 object silicagel columns, with sherwood oil-vinyl acetic monomer for solvent carries out wash-out by the gradient that Shi You Mi ︰ vinyl acetic monomer is 30 ︰ 1 ~ 0 ︰ 1; Collection Shi You Mi ︰ vinyl acetic monomer is that Sephadex LH-20 post crossed by the elutriant of 15 ︰ 1, with Lv Fang ︰ methyl alcohol 1 ︰ 1 for eluent, collects elutriant, obtains white flaky crystals after concentrated.
The concentration of the ethanol described in above-mentioned separation method is volumetric concentration.
Herba Violae Diffusae described in above-mentioned separation method is Violaceae (Violaceae) Viola (Viola) per nnial herb.
Driffractive ring cork alkyl-type triterpenoids of the present invention, has the effect of anti-hepatitis B virus, can be used for the medicine preparing prevention and therapy hepatitis B.Described medicine is by 3,4-driffractive ring friedelane type triterpene compounds shown in (I) formula and the pharmaceutically conventional formulation that forms of acceptable auxiliary material, e.g., and injection, tablet or capsule etc.In described preparation, the weight percentage of the compound shown in (I) formula is 10% ~ 50%.
The technique effect that shown in (I) formula, 3,4-driffractive ring friedelane type triterpene compounds have is proved below by experiment.Adopt the human liver cancer cell HepG2.2.15 of hepatitis B virogene transfection, research compound is on the impact of HBsAg (HBsAg), HbcAg (HBeAg) secretory volume in HepG2.2.15 cell culture supernatant, investigate the Anti-HBV activity effect of compound of the present invention, specific experiment method is as described below.
(1) preparation of pastille nutrient solution
Compound 2 β that following embodiment 1 is obtained, 28 beta-hydroxies-3,4-splits the mother liquor being mixed with 100mmol/L after friedelane-27-carboxylic acid dissolves with DMSO respectively, again with high sugared nutrient solution (i.e. perfect medium: containing 10% foetal calf serum, 150 μ g/mL G418, penicillin 100 μ g/mL, 100 μ g/mL Streptomycin sulphates and the 0.3g/L glutamine) dilution of DMEM, be mixed with 100 respectively, 50,25, the pastille nutrient solution of 12.5,6.25,3.125 μm of ol/L totally 6 concentration gradients.
(2) experimental technique
1. cytotoxicity experiment
Mtt assay: with 0.25% trypsinase and 2 ‰ EDTA1:1 mixture slaking single-layer culturing cells, after stopping digestion, adds PBS liquid, repeatedly blows and beats cell dispersion with elbow straw, in the centrifugal 3min of 1000rpm.Supernatant discarded, it is resuspended to add the high sugared nutrient solution of 5mLDMEM, is made into individual cells suspension, with 3 × 10 after piping and druming cell dispersion
5individual/mL is inoculated in 96 well culture plates, every pore volume 100 μ L.Culture plate is put into 37 DEG C, 5%CO
2incubator in cultivate 24h, after cell is completely adherent, add the pastille nutrient solution (experimental group) of different concns, normal nutrient solution (blank group), 1 ‰ DMSO solution (DMSO control group), experimental group, blank group and DMSO control group often group establish 4 multiple holes, drug control group is (acellular, only add the pastille nutrient solution of different concns) establish 1 multiple hole, cultivate 3d for each group simultaneously.Suck supernatant liquor, every hole adds 5g/L MTT20 μ L, hatches 4h for 37 DEG C, and inhale and abandon supernatant liquor, every hole adds DMSO150 μ L, is placed in by culture plate on oscillator and shakes 10min, and crystallisate is fully dissolved.Microplate reader is surveyed each hole OD value, measures wavelength 570nm, record result, calculates cell survival rate and half toxic concentration (TC
50).
Cell survival rate (%)=(OD
experimental group/ OD
blank group) × 100%
Half toxic concentration (TC
50)=Anti log [inhibition percentage × C of inhibition percentage/(A-B) of logB+ (50-B)] (A≤suppress 50% drug level, B≤suppress 50% drug level, C=log extension rate), with reference to Reed-Muench method.
2. to the Inhibition test of HBeAg, HBsAg
Euzymelinked immunosorbent assay (ELISA): get cell conditioned medium liquid, adopt euzymelinked immunosorbent assay (ELISA), with hepatitis B surface antigen and e antigen detection kit by specification operation, in microplate reader using 630nm as with reference to wavelength, 490nm for determined wavelength measures each hole OD value.Calculating antigen inhibiting rate and medicine are to the half-inhibition concentration (IC of antigen
50).
Medicine is to inhibiting rate (%)=(1-OD of antigen
experimental group/ OD
blank group) × 100%
Medicine is to the half-inhibition concentration (IC of antigen
50)=Anti log [inhibition percentage × C of inhibition percentage/(A-B) of logB+ (50-B)] (A≤suppress 50% drug level, B≤suppress 50% drug level, C=log extension rate), with reference to Reed-Muench method.
3. statistical analysis
Experimental data with
(mean ± standard deviation) represents, statistical study adopts SPSS13.0 statistical software.The OD value of same compound between different concns group, carries out one-way analysis of variance (One-way ANOVA): adopt the inspection of LSD method when variance is neat after homogeneity test of variance; Dunnett ' s T3 method is adopted during heterogeneity of variance.Significance level gets α=0.05, during with P<0.05, judges that group difference has statistical significance.
4. therapeutic index is calculated
Have obvious restraining effect to the secretion of HBeAg or HBsAg, and inhibiting rate and drug level are the compound of typical amount effect relationship, its external Anti-HBV activity URIN Treatment index (TI) is evaluated.
Therapeutic index (TI)=TC
50/ IC
50, wherein TI≤2 are effective low toxicity; 1 < TI < 2 is that poor efficiency is poisonous; TI≤1 is toxicity.TI numerical value more large compound is safer.
(3) experimental result and discussion
By experimental data after above-mentioned statistical procedures result as shown in following table 1 ~ 3.
Table 1 cytotoxicity experiment result
*: P<0.05 when comparing with blank group
The Inhibition test result of table 2 couple HBeAg, HBsAg
*: P<0.05 when comparing with blank group
Table 3TC
50, IC
50with TI value
Above-mentioned experimental result shows 2 β of the present invention, and 28 beta-dihydroxyies-3,4-split friedelane-27-carboxylic acid and have Anti-HBV effect, are all greater than 2 to the TI of HBeAg, HBsAg, can be used for treatment and the prophylactic agent of preparing hepatitis B.
Accompanying drawing explanation
Fig. 1 compound of the present invention
1h-NMR schemes (500MHz).
Fig. 2 compound of the present invention
13c-NMR schemes (150MHz).
The DEPT figure of Fig. 3 compound of the present invention.
The HSQC NMR of Fig. 4 compound of the present invention schemes.
The HMBC NMR of Fig. 5 compound of the present invention schemes.
The NOE NMR of Fig. 6 compound of the present invention schemes.
Embodiment
Following experiment Herba Violae Diffusae (Viola diffusa Ging) herb picks up from Fujian Province's Yongchun County.
Example 1:
One, the preparation of compound
(1) get dry Herba Violae Diffusae herb 10kg, use 120L successively, 100L and 80L concentration is the alcohol reflux Herba Violae Diffusae herb 2h of 95%, merges ethanol extract, reclaims ethanol and is evaporated to without alcohol taste, obtaining total medicinal extract;
(2) be dissolved in the water by total medicinal extract, then, use the water saturated n-butanol extraction of 1.4L sherwood oil, 3L vinyl acetic monomer and 3L 3 times successively, get butanol extraction liquid, concentrating under reduced pressure, except desolventizing, obtains n-butyl alcohol extract 168g;
(3) getting n-butyl alcohol extract 84g is dissolved in 600ml water, crosses D-101 type macroporous resin column, successively with ethanol, concentration that water, concentration are 10% ethanol that is 30%, the concentration ethanol that is 60%, concentration be 90% ethanol and concentration be the ethanol elution of 95%; Collect concentration be 90% ethanol eluate cross 200 ~ 300 object silicagel columns, with sherwood oil-vinyl acetic monomer for solvent carries out wash-out by the gradient that Shi You Mi ︰ vinyl acetic monomer is 30 ︰ 1 ~ 0 ︰ 1; Collection Shi You Mi ︰ vinyl acetic monomer is that Sephadex LH-20 post crossed by the elutriant of 15 ︰ 1, with Lv Fang ︰ methyl alcohol 1 ︰ 1 for eluent, collects elutriant, obtains white flaky crystals 25mg after concentrated.
Two, the qualification of compound
The white particulate crystallization obtained, is soluble in chloroform, is insoluble in methyl alcohol.HR-ESI-MS m/z503.3393 [M]
-, determine that its molecular formula is C
30h
48o
6, degree of unsaturation is 7.After testing, its
1h-NMR,
13c-NMR data are as follows:
1H-NMR（500MHz，DMSO）δ/ppm:4.41(1H,dd,J=12.0,2.0Hz,H-2)，4.38(1H,q,J=6.5Hz,H-4)，1.05(3H,d,J=6.5Hz,CH
3-23)，0.72(3H,s,CH
3-24)，0.79(3H,s,CH
3-25)，0.96(3H,s,CH
3-26)，3.27(dd,J=10.0,4.0Hz,H-28a),3.47(dd,J=10.0,4.0Hz,H-28b)，0.92(3H,s,CH
3-29)，0.91(3H,s,CH
3-30)。
13C-NMR(125MHz，DMSO)δ/ppm:29.3(C-l)，68.0(C-2)，175.4(C-3)，82.3(C-4)，39.9(C-5)，37.4(C-6)，17.7(C-7)，52.3(C-8)，37.5(C-9)，59.7(C-10)，37.4(C-11)，27.2(C-12)，52.8(C-13)，38.5(C-14)，31.8(C-15)，28.1(C-16)，35.3(C-17)，38.7(C-18)，34.5(C-19)，28.4(C-20)，30.2(C-21)，32.8(C-22)，16.0(C-23)，13.1(C-24)，18.5(C-25)，21.2(C-26)，177.5(C-27)，65.5(C-28)，31.6(C-29)，34.6(C-30)。
See Fig. 1 ~ 6,
1show 6 methyl in H-NMR, comprise 3 unimodal [δ of angular methyl(group)
h: 0.72 (3H, s, CH
3-24), 0.79 (3H, s, CH
3-25), 0.96 (3H, s, CH
3-26)], 2 unimodal [δ of gem-dimethyl
h: 0.92 (3H, s, CH
3-29), 0.91 (3H, s, CH
3-30)] and one bimodal δ of methyl
h1.05 (3H, d, J=6.5Hz, CH
3-23); And at δ
h: there are 4 even oxygen protons in 3.2 ~ 4.5 regions: wherein 2 is methyne [δ
h: 4.38 (q, J=6.5Hz, H-4), 4.41 (dd, J=12.0,2.0Hz, H-2)], one is methylene radical [δ
h: 3.27 (dd, J=10.0,4.0Hz, H-28a), 3.47 (dd, J=10.0,4.0Hz, H-28b)].By
13c-NMR with DEPT spectrum is determined in molecule containing 6 methyl, 11 methylene radical (δ that to be connected with oxygen
c65.5) and 5 methynes, wherein 2 (δ that are connected with oxygen
c: 82.3,68.0), 8 quaternary carbons (comprise 2 carbonyl carbon δ
c: 175.4,177.5), be triterpene compound by above-mentioned this structure of feature initial guess.
Containing oxygen proton δ in HMBC spectrum
h4.38 (1H, q, J=6.5Hz, H-4) and δ
c16.0 are correlated with, and from HSQC, this is the bimodal δ of methyl
hcarbon on 1.05 (3H, d, J=6.5Hz), can be released containing oxygen methyne and CH by coupling constant and peak shape
3be connected, carbonyl δ in HMBC
c175.4 have coherent signal with H-1, H-2 and H-4.In addition, H-10 and C-1, C-2 is also had; H-4 and C-10; The long-range coherent signal such as H-24 to C-4, C-5, C-10, by above nuclear magnetic data and long-range relevant deducibility, this new compound is one 3,4-and splits cork alkane type triterpenoid.By consulting literatures [Patra A, Chaudhuri S K, Acharyya A K.Applications of Two-Dimensional NMR in Spectral Assignments of Some Friedelanes andSecofriendelanes.Magnetic Resonance in Chemistry, 1990,28:85-92] find, compared with new compound is composed with the carbon of 2 α-hydroxyfriedelolactone, many carbonyl signals δ 177.5, and lacked a methyl signals δ 18.5, many one containing Oxymethylene carbon signal δ
c65.5 and a few methyl signals δ
c32.0, the C-13 of new compound moves (+13.6ppm) to low field simultaneously, C-12 moves (-3.4ppm) to High-Field, C-17 moves (+5.4ppm) to low field, C-16, C-18, C-22 move (-7.8 ,-4.0 ,-6.3ppm) respectively to High-Field, the above-mentioned data of comprehensive analysis, preliminary deduction new compound is the product that C-27 methyl is oxidized to carboxyl, C-28 methyl is oxidized to methylol of 2 α-hydroxyfriedelolactone.
Compared with 2 α-hydroxyfriedelolactone, C-1 moves (+4.1ppm) to low field, and C-2 moves (-4.5ppm) to High-Field, and deduction new compound C-2 configuration is contrary with 2 α-hydroxyfriedelolactone is beta comfiguration.From NOESY, observe H-2 and H-4 and H-10 have obvious NOESY effect, prompting three is positioned at same side, and confirmation C-2-OH is beta comfiguration.In addition, H-26 and H-25 and H-28 all has obvious NOESY effect, determines 25,26-CH
3, 28-CH
2oH is beta comfiguration.According to document [Baas W J.Naturally occurring seco-ring-A-triterpenoids and their possiblebiological significance.Phytochemistry1985,24 (9): 1875-89] and middle growing stage, determine that C-27-COOH is positioned at C-13 α position.Identify that the structural formula of driffractive ring friedelane prepared by the present invention is for shown in (I) formula thus, its name is called 2 β, 28 beta-dihydroxyies-3,4-splits friedelane-27-carboxylic acid, English name is 2 β, 28 β-dihydroxy-3,4-seco-friedelolactone-27-oic acid.
Example 2:(injection)
Get and adopt the compound 1000mg that described in above-described embodiment 1, method obtains, add the water for injection of 1000ml, with sodium carbonate adjust pH to 7 ~ 7.5, be stirred to dissolve, degerming filtration, embedding, through 100 DEG C of 15 minutes flowing steam sterilizations, make the injection liquid that often props up 2mg/2ml for injection.
Example 3:(capsule)
Get the auxiliary materials such as the compound 5000mg that adopts method described in above-described embodiment 1 to obtain and 4000mg Microcrystalline Cellulose, 500mg sodium starch glycolate, 400mg sodium lauryl sulphate fully to mix, roll-in method is adopted to carry out dry granulation, mix with appropriate Magnesium Stearate again, be packed into 3# Capsules, making specification is that the capsule of 100mg/ grain is for orally using.
Example 4:(tablet)
Get and adopt the compound 5000mg that described in above-described embodiment 1, method obtains to mix with 4000mg starch, 200mg cross-linked pvp, 300mg sodium starch glycolate, with 75% ethanolic soln of 5%PVP as tackiness agent, softwood processed, granulate with 18 mesh sieves, 1h after 60 DEG C of dryings, adds appropriate talcum powder after the whole grain of 20 order, mixing, compressing tablet, making specification is that the tablet of 100mg/ sheet is for orally using.
Claims (5)
1. a driffractive ring friedelane type triterpene compound, shown in the following formula I of its molecular structure:
2. the preparation method of 3,4-driffractive ring friedelane type triterpene compounds according to claim 1, the method is made up of lower step:
(1) get Herba Violae Diffusae, be the alcohol reflux 2h of 95% successively by the concentration of 12,10 and 8 times, merge ethanol extract, reclaim ethanol and be also evaporated to without alcohol taste, obtain total medicinal extract;
(2) total medicinal extract is dissolved in the water, then, uses sherwood oil, vinyl acetic monomer and water saturated n-butanol extraction successively, get butanol extraction liquid, be evaporated to removal solvent, obtain n-butyl alcohol extract;
(3) n-butyl alcohol extract is dissolved in water, crosses D-101 type macroporous resin column, successively with ethanol, concentration that water, concentration are 10% ethanol that is 30%, the concentration ethanol that is 60%, concentration be 90% ethanol and concentration be the ethanol elution of 95%; Collect concentration be 90% ethanol eluate cross 200 ~ 300 object silicagel columns, with sherwood oil-vinyl acetic monomer for solvent carries out wash-out by the gradient that Shi You Mi ︰ vinyl acetic monomer is 30 ︰ 1 ~ 0 ︰ 1; Collection Shi You Mi ︰ vinyl acetic monomer is that SephadexLH-20 post crossed by the elutriant of 15 ︰ 1, take Lv Fang ︰ methyl alcohol as the eluent of 1 ︰ 1, collects elutriant, obtain white flaky crystals after concentrated.
3. 3, the 4-application of driffractive ring friedelane type triterpene compound in the medicine preparing prevention and therapy hepatitis B according to claim 1.
4. the medicine of a prevention and therapy hepatitis B, this medicine is by according to claim 13,4-driffractive ring friedelane type triterpene compound and pharmaceutically acceptable auxiliary material composition, the weight percentage of 3,4-wherein said driffractive ring friedelane type triterpene compounds is 10% ~ 50%.
5. the medicine of prevention and therapy hepatitis B according to claim 4, is characterized in that, described medicine is injection, oral tablet or capsule.
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| CN101190281A (en) * | 2006-11-27 | 2008-06-04 | 杭州尤美特科技有限公司 | Prune tree extract and preparation method and application thereof |
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| CN101190281A (en) * | 2006-11-27 | 2008-06-04 | 杭州尤美特科技有限公司 | Prune tree extract and preparation method and application thereof |
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