CN105153263A - New limonin compound as well as preparation method and medical application thereof - Google Patents
New limonin compound as well as preparation method and medical application thereof Download PDFInfo
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Abstract
The invention discloses a new limonin compound as well as a preparation method and medical application thereof, belonging to the field of medicines. The invention in particular relates to a new limonin compound separated from the dry root bark of dictamnus dasycarpus Turcz., a preparation method and a medical application. The compound is reported for the first time, can be extracted, separated and purified from the dry root bark of dictamnus dasycarpus Turcz. and has high purity. Tests prove that the new limonin compound has obvious proliferation inhibition effects on the cell MiaPaCa-2 of human pancreatic cancers under the condition of anaerobic culture, has more obvious inhibiting effects with increase of the concentration and the action time and can be developed to prepare drugs for treating pancreatic cancers.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to be separated a kind of new limonoid obtained and preparation method thereof and medicinal use from the dry root skin of shaggy-fruited dittany.
Background technology
Shaggy-fruited dittany (DictamnusdasycarpusTurcz.) is under the jurisdiction of Rutaceae (Rutaceae) shaggy-fruited dittany and belongs to (DictamnusL.), for perennial herbaceous plant, plant materials has strong peat-reek, is mainly distributed in Europe and parts of Asia.About 5 kinds, this genus whole world, Chinese Plants will records a kind.Record record according to history tree and " Chinese Pharmacopoeia " 2010 editions, Dictamnus dasycarpus Turcz is the dry root skin of Rutaceae shaggy-fruited dittany platymiscium shaggy-fruited dittany, is Chinese conventional Chinese medicine, has another name called northern fresh hide, Root of Flatspine Pricklyash skin, smelly skin etc.Modern pharmacology research shows, Dictamnus dasycarpus Turcz has heat-clearing and damp-drying drug, dispelling wind and arresting itching and the effect such as removing toxic substances, the diseases such as yellow water is dripping in order to treat, eczema, beriberoid pyretic arthralgia, mange sore leprosy, jaundice urine is red, thus causes extensive concern.
At present, go out number of chemical composition from dittany root skin and over-ground part isolation identification, comprise the composition such as volatile oil, alkaloids, limonin, compound of polysaccharide and tonka bean camphor, flavonoid, steroid.Alkaloid contained in Root-bark of Densefruit Pittany is furoquinoline Alkaloid, mainly contain dictamine, β-fagarine, trigonelline, choline, γ-fagarine, different spot Buddhist woods potash, 7,8-dimethoxymyrtopsine, O-ethylnor-γ-fagarine, platydesmine, O-ethylnordictamine, O-ethylnorskimmianin, 7,8-dimethoxyplatydesmine etc., wherein dictamine is one of index components of Root-bark of Densefruit Pittany.In addition, limonoid is the compounds the most widely that distributes in shaggy-fruited dittany platymiscium, is a large class important activity composition in Root-bark of Densefruit Pittany.
Shaggy-fruited dittany plant materials volatile oil material such as sesquiterpenoids etc. has antitumor hyperplasia and cellular cytoxicity activity, it has obvious restraining effect to the growth of 6 kinds of tumor cell lines, as human breast tumor's cell strain (MCF-7, ZR-75-30 and MDA-MB-435S), human liver JEG-3 (Bel-7402 and HepG2) and human adrenal cells's cell strain (ACHN).In addition, in Root-bark of Densefruit Pittany, volatile oil also has strong suppression Methicillin-resistant Staphylococcus aureus and the activity of streptococcus aureus ATCC25923.Alkaloid has the effects such as cardiac stimulant, anti-inflammatory, vasoconstriction unstriated muscle, resisting pathogenic microbes.Wherein, dictamine is its important activity composition, has the multiple biological activitys such as antibacterial, antiviral and skin eczema, skin pruritus and Anticancer Activity in vitro.The bitter chlorins compound fraxinellone of lemon in Root-bark of Densefruit Pittany has Anticancer Activity in vitro, and can be used as a kind of novel hepatosis treating medicine, has good protecting liver, lowering enzymes and suppresses the effects such as hepatic fibrosis.Pharmacological evaluation shows, Root-bark of Densefruit Pittany Crude polysaccharides obviously can increase the weight of normal mouse Thymus and spleen, improves reticuloendothelial system phagocytic function; there is antifatigue, hypoxia tolerance, raising resisting stress capability; can significantly promote mouse choleresis, accelerate poisonous substance excretion in liver, thus protection liver.
Summary of the invention
The object of the present invention is to provide and a kind ofly from the dry root skin of shaggy-fruited dittany, be separated a kind of new limonoid obtained;
Another object of the present invention is to the preparation method that this new compound is provided;
Another object of the present invention is the medicinal use providing this compound for the preparation for the treatment of pancreatic cancer drug.
Above-mentioned purpose of the present invention is achieved by technical scheme below:
There is the compound (I) of following structural formula,
The preparation method of described compound (I), comprise following operation steps: the dry root skin of (a) shaggy-fruited dittany is pulverized, extract with 85% alcohol heat reflux, united extraction liquid, be concentrated into without alcohol taste, use sherwood oil, ethyl acetate and water saturated n-butanol extraction successively, obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; Acetic acid ethyl ester extract macroporous resin removal of impurities in (b) step (a), use 10% ethanol and 75% ethanol elution successively, collect 75% ethanol eluate, concentrating under reduced pressure obtains 75% ethanol elution thing medicinal extract; C in () step (b), 75% ethanol elution medicinal extract purification on normal-phase silica gel is separated, obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 90:1,40:1,20:1,10:1 and 1:1; D in () step (c), component 3 is separated further by purification on normal-phase silica gel, obtain 3 components successively with the methylene chloride-methanol gradient elution that volume ratio is 25:1,20:1 and 10:1; E in () step (d), component 2 reverse phase silica gel of octadecylsilane bonding is separated, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collect 10-12 column volume elutriant, elutriant concentrating under reduced pressure obtains pure compound (I).
Further, described macroporous resin is AB-8 type macroporous adsorbent resin.
Pharmaceutical composition, the described compound (I) wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
The application of described compound (I) in the medicine of preparation treatment carcinoma of the pancreas.
The application of described pharmaceutical composition in the medicine of preparation treatment carcinoma of the pancreas.
When the compounds of this invention is used as medicine, directly can uses, or use with the form of pharmaceutical composition.
This pharmaceutical composition contains the compounds of this invention (I) for the treatment of significant quantity, and all the other are acceptable on pharmacology, nontoxic to humans and animals and pharmaceutically acceptable carrier of inertia and/or vehicle.
Described pharmaceutically acceptable carrier or vehicle are that one or more are selected from solid, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent.Pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention is applied to by form that is oral or injection the patient needing treatment.For time oral, tablet, slow releasing tablet, controlled release tablet, capsule, dripping pill, micropill, suspensoid, emulsion, powder or granule, oral liquid etc. can be made into; During for injecting, can be made into water-based or oily solution, aseptic powder injection, liposome or the emulsion etc. of sterilizing.
Figure of description
Fig. 1 is compound (I) structural formula;
Fig. 2 is that the theoretical ECD value of compound (I) compares with experiment ECD value.
Embodiment
Further illustrate essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.Although be explained in detail the present invention with reference to preferred embodiment, those of ordinary skill in the art should be appreciated that and can modify to technical scheme of the present invention or equivalent replacement, and does not depart from essence and the scope of technical solution of the present invention.
Embodiment 1: compound (I) is separated preparation and structural identification
Medicinal material and reagent source: ethanol, sherwood oil, ethyl acetate, propyl carbinol, methylene dichloride are analytical pure, purchased from Shanghai Ling Feng chemical reagent company limited, methyl alcohol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.The dry root skin of shaggy-fruited dittany purchased from Hui nationality's Chinese Medicinal Materials Markets, Fujian, the place of production.
Preparation method: the dry root skin (10kg) of (a) shaggy-fruited dittany is crushed to mung bean size, (25L × 3 time) are extracted with 85% alcohol heat reflux, united extraction liquid, be concentrated into without alcohol taste (3L), sherwood oil (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated propyl carbinol (3L × 3 time) is used to extract successively, concentrated, obtain petroleum ether extract, acetic acid ethyl ester extract (305g) and n-butyl alcohol extract respectively; B in () step (a), acetic acid ethyl ester extract dissolved in purified water is to 2L, medical absorbent cotton filters, filtrate is separated with AB-8 type macroporous resin, use 10% ethanol (10L) and 75% (12L) ethanol elution successively, collect 75% ethanol eluate, concentrating under reduced pressure obtains 75% ethanol elution thing medicinal extract (142g); C in () step (b), 75% ethanol elution medicinal extract 200-300 order purification on normal-phase silica gel is separated, successively with volume ratio be 90:1 (10 column volumes), the methylene chloride-methanol gradient elution of 40:1 (10 column volumes), 20:1 (8 column volumes), 10:1 (8 column volumes) and 1:1 (5 column volumes) obtains 5 components; D component 3 (35g) 200-300 order purification on normal-phase silica gel is separated further in () step (c), successively with volume ratio be 25:1 (10 column volumes), the methylene chloride-methanol gradient elution of 20:1 (10 column volumes) and 10:1 (5 column volumes) obtains 3 components; E in () step (d), component 2 (10g) the reverse phase silica gel ODS-C18 of octadecylsilane bonding is separated, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collect 10-12 column volume elutriant, elutriant concentrating under reduced pressure obtains pure compound (I) (24mg).
Structural identification: HR-ESIMS shows [M+Na]
+for m/z707.3408, can obtain molecular formula in conjunction with nuclear-magnetism feature is C
38h
52o
11, degree of unsaturation is 13.Hydrogen nuclear magnetic resonance modal data δ
h(ppm, DMSO-d
6, 400MHz): H-1 (3.45, ddd, J=8.6, 3.3, 2.2), H-2 (1.93, m), H-2 (2.25, ddd, J=16.4, 3.3, 2.6), H-3 (5.05, dd, J=2.6, 2.6), H-5 (2.28, d, J=12.6), H-6 (4.15, dd, J=12.6, 2.9), H-7 (5.64, d, J=2.9), H-9 (2.94, dd, J=12.9, 7.1), H-11 (1.57, 2.30, m), H-12 (5.10, d, J=8.4), H-15 (5.97, s), H-17 (3.63, s), H-18 (1.00, s), H-19 (0.88, s), H-21 (7.30, m), H-22 (6.07, br, s), H-23 (7.29, m), H-28 (3.21, br, d, J=7.9), H-28 (3.43, d, J=7.9), H-29 (1.10, s), H-30 (1.31, s), H-3 ' (6.70, br, q, J=7.2), H-4 ' (1.69, br, d, J=7.2), H-5 ' (1.72, br, s), H-2 " (2.09, m), H-3 " (1.24, 1.53, m), H-4 " (0.70, t, J=7.4), H-5 " (0.95, d, J=7.0), 12-OAc (2.11, s), 1-OH (3.58, s), 6-OH (3.58, s), 28-OH (3.65, s), carbon-13 nmr spectra data δ
c(ppm, DMSO-d
6, 125Hz): 70.4 (CH, 1-C), 29.3 (CH
2, 2-C), 72.3 (CH, 3-C), 41.6 (C, 4-C), 39.8 (CH, 5-C), 71.2 (CH, 6-C), 72.0 (CH, 7-C), 45.0 (C, 8-C), 33.4 (CH, 9-C), 39.1 (C, 10-C), 23.4 (CH
2, 11-C), 69.6 (CH, 12-C), 50.2 (C, 13-C), 187.1 (C, 14-C), 125.2 (CH, 15-C), 203.6 (C, 16-C), 51.7 (CH, 17-C), 23.9 (CH
3, 18-C), 14.7 (CH
3, 19-C), 117.1 (C, 20-C), 141.2 (CH, 21-C), 110.2 (CH, 22-C), 142.0 (CH, 23-C), 77.0 (CH
2, 28-C), 18.1 (CH
3, 29-C), 23.8 (CH
3, 30-C), 165.5 (C, 1 '-C), 127.0 (C, 2 '-C), 137.7 (CH, 3 '-C), 13.7 (CH
3, 4 '-C), 11.3 (CH
3, 5 '-C), 174.0 (C, 1 "-C), 40.9 (CH, 2 "-C), 25.8 (CH
2, 3 " and-C), 11.1 (CH
3, 4 " and-C), 16.6 (CH
3, 5 " and-C), 170.0 (C, 12-OAc), 21.5 (CH
3, 12-OAc), carbon atom mark is see Fig. 1.NMR data show the α that this compound contains, beta-unsaturated carbonyl, the furyl that a 3-replaces, 2-methyl-2, a 3 alkene-butylene acyloxy, a 2-methylbutyryl oxygen base group, five contain oxygen methyne, and 1 containing Oxymethylene and an acetoxyl group.2-methylbutyryl oxygen is connected based on C-3, the above-mentioned conclusion of relevance verification of H-3 (δ H5.05) and ester carbonyl group carbon (δ C174.0) in HMBC spectrum.In HMBC spectrum, the dependency of H-7 (δ H5.64) and ester carbonyl group carbon (δ C174.0) shows that C-7 position is connected with 2-methyl-2,3 alkene-butylene acyloxy.In HMBC spectrum, H-12 (δ H5.10) shows C-12 position to be connected with an acetoxyl group with the dependency of corresponding esters carbonyl carbon (δ C170.0).In addition, the chemical shift of C-1 (δ C70.4), C-6 (δ C71.2) and C-28 (δ C77.0) indicates the existence of 1-OH, 6-OH and 28-OH.In ROESY spectrum, Me-29 and H-2 β, H-6 and Me-19; Me-19 and H-2 β, H-6 and Me-30 and Me-30 and H-6NOE signal strengthen, and show H-2 β, H-6, Me-19, Me-29, and Me-30 are beta comfigurations, thus make the hydroxyl of 6 be α configuration.In addition, J
5,6(12.6Hz) coupling constant shows that H-5 is α configuration, thus to establish H-9 and Me-18 be α configuration, the above-mentioned inference of H-9 and H-5 and Me-18 relevance verification in ROESY spectrum.In addition, J
1,2 β(3.3Hz), J
2 β, 3(2.6Hz) and J
6,7(2.9Hz) less coupling constant shows H-1, H-3 and H-7 is beta comfiguration, thus 1,3,7 remaining substituted radicals are α configuration.In ROESY spectrum, between H-12 and Me-18 (δ H1.00), stronger dependency shows that 12-OAc is beta comfiguration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine this compound as shown in Figure 1, steric configuration is determined further by ECD test, theoretical value and experimental value basically identical (Fig. 2).
Embodiment 2: compound (I) pharmacological action is tested
One, material and instrument
Human pancreas cancer MiaPaCa-2 cell is so kind as to give by institute of oncology of Tumour Hospital Attached To Tianjin Medical Univ..Compound (I) is made by oneself, and HPLC normalization method purity is greater than 98%.FBS, trypsinase-EDTA Digestive system are purchased from Hyclone company of the U.S..PBS powder is purchased from Tianjin Run Tai development in science and technology company limited.DMEM low sugar nutrient solution is purchased from Gibco company of the U.S..MTT is purchased from Sigam company of the U.S..DMSO is purchased from Beijing Chemical Plant.Benzylpenicillin sodium for injection is purchased from HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory.Streptomycin sulphate for injection is purchased from Dalian Merro Pharmaceutical Co., Ltd..
Bechtop, cell culture incubator (Thermo company of the U.S.).4 DEG C of refrigerators ,-20 DEG C of refrigerators (Qingdao company of Haier).-80 DEG C of refrigerators (FormaScientific).Electric drying oven with forced convection (Tianjin laboratory apparatus factory).Opticmicroscope (Japanese Olympus company).Inverted phase contrast microscope (German leica company).Hypervelocity refrigerated centrifuge (HIT).Microplate reader (Shanghai Kehua Bio-engineering Co., Ltd).E-Centrifuge (Wealtec), micro sample adding appliance (German Eppendorf), electronic thermostatic water-bath (Yuyao City east electric instrument factory), high-pressure sterilizing pot (Shandong Medical Devices Co., Ltd. of Xinhua), electronic balance (Shanghai balance equipment factory).
Two, test method
1, cell cultures:
(1) normal oxygen is cultivated: human pancreas cancer MiaPaCa-2 cell is put into 5%CO
2, 37 DEG C, the CO of saturated humidity
2adherent culture in incubator, changes nutrient solution in good time, cell attachment growth merge to 80% ~ 90% time go down to posterity.
(2) anoxic is cultivated: human pancreas cancer MiaPaCa-2 cell is placed on 5%CO
2, 94%N
2, 1%O
2, 37 DEG C, cultivate in the anoxic cell of saturated humidity.Anoxic cell is set up: hypoxia device is adjustable culture vessel, has an air inlet port and a production well.During experiment, anoxic cultured cells is put into adjustable culture vessel, be filled with low-oxygen gas mixture body (5%CO by air inlet port
2+ 95%N
2+ 1%O
2), record little indoor oxygen concentration and maintain after 1% airtight, move in cell culture incubator, 37 DEG C of cultivations.Every 24h qi of chong channel ascending adversely and ventilation once rearmounted 37 DEG C of incubators continuation cultivation again, collects each group of cell, respectively for MTT experiment after 24h, 48h, 72h.
2, the detection of cell proliferation
(1) collect logarithmic phase MiaPaCa-2 cell, be prepared into single cell suspension and count, adjustment concentration is with every hole 5 × l0
3individual cell is inoculated in 96 porocyte culture plates, and every hole cumulative volume 100 μ L (the aseptic PBS of marginal pore same volume fills), in 5%CO
2, 37 DEG C, the CO of saturated humidity
2cultivate in incubator, after cell formation individual layer, abandon supernatant give different concns Rhein process.
(2) blank group (not adding the equal-volume nutrient solution of drug treating) and Rhein medicine 20 μm of ol/L, 40 μm of ol/L, 80 μm of ol/L are divided), often group establishes 6 parallel holes, and experiment in triplicate, inserts 37 DEG C, 5%CO
2, 94%N
2, 1%O
2anoxic cell in cultivate 24h, 48h, 72h respectively.
(3) after rinsing 96 porocyte culture plate 2 times gently with PBS, every hole adds l0 μ LMTT (5mg/mL), centrifugally after continuing to cultivate 4h abandons supernatant, and every hole adds the DMSO of 15 μ L, puts 15min that shaking table vibrates, crystallisate is fully dissolved.
(4) enzyme-linked immunosorbent assay instrument measures the absorbance (A value) in each hole in 570nm place, calculates cell proliferation inhibition rate.
(5) inhibiting rate (%)=(blank group average A-value-medicine group average A-value)/blank group average A-value × 100%.
(6) take concentration as transverse axis, inhibiting rate (%) is longitudinal axis drafting inhibiting rate histogram.
3, statistical method
Adopt SPSS17.0 statistical software process, measurement data measurement data meets normal distribution, with mean scholar standard deviation
represent, comparing between mean and adopt one-way analysis of variance or t inspection, is that difference has statistical significance with P<0.05.
Three, result and conclusion
MTT result shows: when (1) compound (I) intervenes human pancreas cancer MiaPaCa-2 cell same equal time (24h, 48h, 72h), along with the increase of compound (I) concentration (in experimental concentration scope), OD value corresponding to it is less, when showing that compound (I) is identical to human pancreas cancer MiaPaCa-2 cell intervention time under anoxic conditions, along with the increase of drug level, cell survival rate reduces.The results are shown in Table 1 (note:
ap<0.01VS control group;
bp<0.01VS20 μm of ol/L group;
cp<0.01VS40 μm of ol/L group).
(2) after (20 μm of ol/L, 40 μm of ol/L, 80 μm of ol/L) compound (I) of different concns intervenes human pancreas cancer MiaPaCa-2 cell 48h, under different concns effect, cell proliferation inhibition rate is respectively (20.13 ± 0.80) %, (34.83 ± 0.66) %, (45.68 ± 1.45) %, inhibiting rate increases in rising trend with drug level, and group difference has statistical significance (P<0.05).After compound (I) intervention carcinoma of the pancreas MiaPaCa-2 cell 24h, 48h, 72h of 80 μm of ol/L, MiaPaCa-2 inhibitory rate of cell growth is respectively (38.78 ± 0.92) %, (45.68 ± 1.45) %, (55.95 ± 2.20) %, increase in time-dependent manner, group difference has statistical significance (P<0.05).The results are shown in Table 2 (note:
ap<0.01VS control group;
bp<0.01VS20 μm of ol/L group;
cp<0.01VS40 μm of ol/L group).
Conclusion, compound (I) has obvious inhibited proliferation to human pancreas cancer MiaPaCa-2 cell under anoxic culture condition, along with increase and the prolongation of action time of compound (I) concentration, restraining effect is more obvious, i.e. lifetime-dose-dependently within the scope of finite concentration.
Table 1 compound (I) on the impact of human pancreas cancer MiaPaCa-2 Growth of Cells (n=6,
)
Table 2 compound (I) on the impact of human pancreas cancer MiaPaCa-2 inhibitory rate of cell growth (n=6,
)
Embodiment 3
The preparation of tablet: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, vehicle is added, pelletizing press sheet than the ratio for 1:9 in itself and excipient weight.
Embodiment 4
The preparation of oral liquid: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, oral liquid method for making makes oral liquid routinely.
Embodiment 5
The preparation of capsule or granule: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, add vehicle in itself and excipient weight than the ratio for 1:9, make capsule or granule.
Embodiment 6
The preparation of injection liquid: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, inject with water routinely, essence filter, injection liquid is made in embedding sterilizing.
Embodiment 7
The preparation of aseptic powder injection: by embodiment 1 method first obtained compound (I), and the salt utilizing organic acid to make as tartrate or citric acid or formic acid or oxalic acid etc., mineral acid example hydrochloric acid or sulfuric acid or phosphoric acid, be dissolved in sterile water for injection, stirring makes molten, filter with aseptic suction funnel, aseptic essence filter again, be sub-packed in ampoule, after frozen drying, aseptic sealing by fusing obtains powder injection.
Claims (6)
1. there is the compound (I) of following structural formula,
2. the preparation method of compound according to claim 1 (I), it is characterized in that comprising following operation steps: the dry root skin of shaggy-fruited dittany is pulverized by (a), extract with 85% alcohol heat reflux, united extraction liquid, be concentrated into without alcohol taste, use sherwood oil, ethyl acetate and water saturated n-butanol extraction successively, obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract respectively; Acetic acid ethyl ester extract macroporous resin removal of impurities in (b) step (a), use 10% ethanol and 75% ethanol elution successively, collect 75% ethanol eluate, concentrating under reduced pressure obtains 75% ethanol elution thing medicinal extract; C in () step (b), 75% ethanol elution medicinal extract purification on normal-phase silica gel is separated, obtain 5 components successively with the methylene chloride-methanol gradient elution that volume ratio is 90:1,40:1,20:1,10:1 and 1:1; D in () step (c), component 3 is separated further by purification on normal-phase silica gel, obtain 3 components successively with the methylene chloride-methanol gradient elution that volume ratio is 25:1,20:1 and 10:1; E in () step (d), component 2 reverse phase silica gel of octadecylsilane bonding is separated, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collect 10-12 column volume elutriant, elutriant concentrating under reduced pressure obtains pure compound (I).
3. preparation method according to claim 2, is characterized in that: described macroporous resin is AB-8 type macroporous adsorbent resin.
4. pharmaceutical composition, the compound according to claim 1 (I) wherein containing treatment significant quantity and pharmaceutically acceptable carrier.
5. the application of compound according to claim 1 (I) in the medicine of preparation treatment carcinoma of the pancreas.
6. the application of pharmaceutical composition according to claim 4 in the medicine of preparation treatment carcinoma of the pancreas.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105399792A (en) * | 2015-12-07 | 2016-03-16 | 西宁意格知识产权咨询服务有限公司 | Novel steroidal compound and preparing method and medical application thereof |
| CN105943533A (en) * | 2016-06-03 | 2016-09-21 | 朱正直 | Application of limonin compound to preparation of medicine for treating pancreatic cancer |
| CN106008549A (en) * | 2016-06-03 | 2016-10-12 | 朱正直 | Limonin compounds and preparation method thereof |
| CN106397369A (en) * | 2016-09-09 | 2017-02-15 | 中国科学院西北高原生物研究所 | Novel labdane-type diterpenoid compound, preparation method and application thereof, pharmaceutical composition and application of pharmaceutical composition |
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Application publication date: 20151216 |