CN103694248B - Antitumor compound extracted from guttifer, and preparation method and application thereof - Google Patents
Antitumor compound extracted from guttifer, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an antitumor compound extracted from guttifer, and a preparation method and application thereof. The preparation method of the compound comprises the following steps: (1) taking the medicinal material guttifer, extracting with ethyl acetate, carrying out silica gel column chromatographic separation on the extract, and carrying out petroleum ether-ethyl acetate gradient elution to obtain 11 components A-K; (2) discarding the grease components and garcinia acid components, carrying out HPLC-PDA-MS (high performance liquid chromatography-potato dextrose agar-Murashige-Skoog) repeat analysis to obtain a key component I; (3) carrying out silica gel column chromatographic separation on the component I, carrying out chloroform-methanol gradient elution to obtain a fraction I-2, collecting one fraction for every 30ml, and merging identical components according to the TLC (thin layer chromatography) result to obtain a fraction I-3; (4) carrying out reversed phase RP-18 separation on I-3, carrying out acetonitrile-water gradient elution, collecting one fraction for every 20ml, and merging identical components to obtain a subfraction I-3E; and (5) carrying out purification and acetonitrile elution on I-3E to obtain the compound. The compound can be used for treating tumors.
Description
Technical field
The present invention relates to pharmaceutical technology field, extract detached compound, system from Chinese crude drug Resina garciniae particularly to one kind
The method of standby described compound, comprise the medical composition of described compound, and prepare antitumor drug using described compound
Purposes.
Background technology
Resina garciniae be Garcinia maingayii Resina garciniae (garcinia hanburyi hook f.) trunk hurt after flow out glue
Shape resin, also known as extra large rattan, beautiful Huang, the moon yellow, cured Huang etc..Original Southeast Asia, China some areas such as Yunnan, Guangxi, Guangdong etc.
There is introducing and planting.
Resina garciniae begins to be loaded in " Haiyao Bencao, Oversea Materia Medica ", and it is cold in nature, sour in the mouth, puckery, pungent, poisonous, has removing blood stasis eliminating stagnation, detoxifies, stops blooding, killing
The effect of worm, the traditional Chinese medical science is used for controlling swollen ulcer drug, stubborn dermatitis malignant boil, bleeding due to trauma, ulcerative gingivitis decayed tooth, burn.
At present, reported and isolated and identified more than 20 compounds from Resina garciniae, be mostly the ton ketone containing bridged ring
(xanthone) class compound, i.e. gambogic acid, Mo Lilin class, guttiferin class, and Resina garciniae aldehyde, betulic acid etc. multipleization
Compound.
Modern pharmacology research shows, Resina garciniae extract has the antibacterial activity of wide spectrum, to staphylococcus aureuses, green pus
Bacillus etc. has stronger bacteriostasis.And, pharmacological evaluation and clinical experience prove, it has antitumor action, can effectively press down
Tumor proliferation processed, has significant curative effect to kinds of tumors.
Inventor extracts, from Resina garciniae, the compounds of this invention obtaining thering is biological activity, has more compared with gamlogic acid
Superior anti-tumor activity.
Content of the invention
The invention provides a kind of extract detached formula (1) compound with biological activity from Resina garciniae, and provide
The preparation method of this compound and the purposes of preparation tumor.
Formula (1) compound has a following formula:
Present invention also offers the preparation method of this formula (1) compound, concretely comprise the following steps:
(1) Resina garciniae medical material ethyl acetate is taken to extract, extract separates through silica gel column chromatography, petroleum ether-ethyl acetate ladder
Degree eluting, obtains 11 component a～k；
(2) discard oil component a, b and Resina garciniae acid constituents d, e, through hplc-pda-ms analysis, obtain emphasis component i；
(3) component i separates through silica gel column chromatography again, chloroform-methanol gradient elution, and every 30ml collects a flow point, merges
11st part to the 16th part eluent, flow velocity is 2ml/min, obtains flow point i-3；
(4) take i-3 inverted rp-18 chromatographic isolation, acetonitrile-water gradient, every 20ml collects a flow point, merges the
13 parts to the 18th part eluents, flow velocity is 2ml/min, obtains Arius and divides i-3e；
(5) i-3e is purified, acetonitrile isocratic elution, obtains formula (1) compound.
Preferably, the ratio of step (1) petrochina ether-ethyl acetate 50～0:1 by volume carries out gradient elution；
It is furthermore preferred that petroleum ether-ethyl acetate is divided into six gradients to carry out eluting, respectively 50:1,10:1,5:1,2:1,
1:1,0:1.
Preferably, in step (3), the ratio of chloroform-methanol 50～10:1 by volume carries out gradient elution；
Preferably, in step (4), the ratio of acetonitrile-water 40～90:60～10 by volume carries out gradient elution；
It is furthermore preferred that acetonitrile-water is divided into five gradients to carry out eluting, respectively 40:60,50:50,60:40,80:20,
90:10.
Preferably, in step (5), the concentration of acetonitrile is 80%～95%；
It is furthermore preferred that the concentration of acetonitrile is 80%～85%.
Inventor by physicochemical property and Modern spectroscopy learn to do section (1H-nmr (Fig. 2),13C-nmr (Fig. 3), hr-esi-ms
、1h-1H cosy and hsqc) Structural Identification has been carried out it was demonstrated that it is change as shown in formula (1) for the structure to the compound separately obtaining
Compound.
In one aspect, formula (1) compound of the present invention can be used for treating tumor disease.Inventor finds of the present inventionization
Compound has the inhibitory activity of wide spectrum to tumor cell.Described tumor disease includes the group selected from consisting of: neuroglia
Glucagonoma, adenocarcinoma of lung and ovarian cancer.
On the other hand, present invention also offers the pharmaceutical composition for the treatment of tumor disease, it comprises therapeutically effective amount
Formula (1) compound, and at least one selected from following pharmaceutically acceptable non-active ingredient: pharmaceutically acceptable
Diluent, pharmaceutically acceptable excipient and pharmaceutically acceptable supporting agent.
Brief description
Fig. 1 is formula (1) structural formula of compound；
Fig. 2 is formula (1) compound1H-nmr composes；
Fig. 3 is formula (1) compound13C-nmr composes.
Specific embodiment
Compound
Formula (1) compound has a structure that
Medical composition/composite
Suitable administration routes are including but not limited to oral, intravenouss, rectum, aerosol, parenteral, eye, pulmonary,
Through mucous membrane, percutaneous, vagina, ear, per nasal, intramuscular injection, subcutaneous injection and topical administration.In addition, only for example, non-warp
Intestinal transmission includes intramuscular, subcutaneous, intravenouss, intramedullary injection, and intrathecal, directly interior, intraperitoneal, lymph is interior and intranasal is noted
Penetrate.
In certain embodiments, compound as herein described is with local rather than systemic manner administration.In other embodiments
In, compound as herein described is with quick release formulation, prolongation release formulation or middle release composite shape
Formula provides.In other embodiments, compound as herein described is local administration.
In certain embodiments, compound as herein described formulated for medical composition.In a particular embodiment, medicine
Compositionss in the usual way, are allocated using one or more physiologically acceptable supporting agents, described are physiologically subjected to
Supporting agent comprise excipient and auxiliary agent, it contributes to reactive compound is processed as can be used for the preparation of pharmacy.Suitably composite
Depend on selected dosing way.
Medical composition refers to the mixture of formula (1) compound and other chemical constituents, described chemical constituent as supporting agent,
Stabilizer, diluent, dispersant, suspending agent, thickening agent and/or excipient.In certain embodiments, medical composition contributes to
To mammal administration compound.
In certain embodiments, compound as herein described formulated for oral administration.Compound as herein described with
Peroral dosage form allocate, only for example, described peroral dosage form include tablet, powder, pill, sugar-coated ingot, capsule, liquid, gel,
Syrup, elixir, serosity, suspension and the like.
In certain embodiments, described medical composition be tablet, capsule, powder ampoule agent for injection, injection, drop pill and
Slow releasing tablet.
In one embodiment, formula (1) compound is allocated in aqueous solution.In a particular embodiment, only for example,
Aqueous solution is selected from physiological compatibility buffer, such as Han Shi liquid (hank ' s solution), ringer's solution (ringer ' s
) or normal saline buffer solution solution.
In other embodiments, formula (1) compound formulated for through mucous membrane dispensing.In a particular embodiment, through mucous membrane
Composite includes the penetrating agent being suitable to be intended to permeability barrier.
In the formulated other embodiments for other parenteral injections of compound as herein described, suitable composite bag
Include aqueouss or non-aqueous solution.
In certain embodiments, by mixing one or more solid excipients and one or more this paper institutes
The compound stated, after optionally grinding gained mixture and adding suitable auxiliary agent when necessary, processing granulate mixture is to obtain piece
Agent or pill are obtaining for the oral pharmaceutical preparation using.Specifically, suitable vehicle is filler, such as sugar, including breast
Sugar, sucrose, Mannitol or Sorbitol；Cellulose preparation, such as corn starch, wheaten starch, rice starch, potato starch, bright
Glue, tragacanth, methylcellulose, Microcrystalline Cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose；Or other materials, such as
Polyvinylpyrrolidone (pvp or polyvidone) or calcium phosphate.In a particular embodiment, optionally add disintegrating agent.Only illustrate
Say, disintegrating agent includes cross-linking sodium carboxymethyl cellulose, Polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.
Peroral dosage form also include from gelatin make with insert capsule, and by gelatin and plasticizer (as glycerol or mountain
Pears alcohol) soft seal capsule made.In a particular embodiment, cooperation insertion capsule contain active component and one or more
The mixture of filler.Only for example, filler includes Lactose, the such as binding agent such as starch and/or as Talcum or magnesium stearate
Deng lubricant, and the stabilizer optionally employing.In other embodiments, soft capsule contains one or more dissolvings or suspends
Reactive compound in suitable liquid.Only for example, appropriate liquid includes one or more fatty oils, liquid paraffin
Or liquid polyethylene glycol.Additionally, optionally add stabilizer.
In other embodiments, formula (1) compound is local administration.The compositionss of local administration can include solution, suspension
Liquid, lotion, gel, paste, swab, balsam, cream or ointment.
In other embodiments, formula (1) compound formulated for inhalation dosing.It is suitable to the various forms bag of inhalation dosing
Include (but not limited to) aerosol, spraying or powder.
In order that those skilled in the art more fully understands technical scheme, with reference to specific embodiment pair
The present invention is described in further detail.There is provided described example to be for illustration purposes only, and be not intended to limit right provided herein
The scope of claim.
The preparation method of embodiment 1 formula (1) compound
(1) extract Resina garciniae medical material (ethyl acetate and Resina garciniae weight than for 15:1) with ethyl acetate, extract is through silicagel column
Chromatographic isolation, six gradient elutions of petroleum ether-ethyl acetate (50:1,10:1,5:1,2:1,1:1,0:1), flow velocity is 2ml/
Min, every 30ml collect a flow point, and every 7 parts of eluents merge, and obtain 11 component a～k successively；
(2) after discarding oil component a and b and Resina garciniae acid constituents d and e, then through hplc-pda-ms analysis, obtain emphasis group
Divide i；
(3) component i separates through silica gel column chromatography again, chloroform-methanol (50:1～10:1) gradient elution, and every 30ml collects one
Individual flow point, merges the 11st part to the 16th part eluent, and flow velocity is 2ml/min, obtains flow point i-3；
(4) i-3 inverted rp-18 chromatographic isolation, acetonitrile-water (40:60,50:50,60:40,80:20,90:10) ladder are taken
Degree eluting, every 20ml collects a flow point, merges the 13rd part to the 18th part eluent, and flow velocity is 2ml/min, obtains Arius and divides i-
3e；
(5) i-3e is purified, 82% acetonitrile isocratic elution, obtains formula (1) compound.Embodiment 2 formula
(1) Structural Identification of compound
This compound is yellow jelly, [α] 24d-116.7 (c0.06, meoh)；1h and13C nmr data is shown in Table 1；
uv(meoh)λmax318,276nm；ir(kbr)vmax3431,2970,2927,1740,1689,1627,1587,1441,1377,
1325,1176,1113,955nm；Hr-tof-ms shows quasi-molecular ion peak m/z699.3150 (calcd for
c39h48o10Na, 699.3145).
Table 1 formula (1) compound nuclear magnetic data (1H (500mhz, cdcl3),13C (100mhz, cdcl3)nmr)
Embodiment 3
The inhibitory action to human lung cancer transplanted tumor for formula (1) compound
1. materials and methods
1.1 tested material
Formula (1) compound: 10mg/ml, purity 97%, lot number 20100121, by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences
Preparation.
Vinorelbine Tartrate Injection (Gai Nuo): Jiangsu Haosen Pharmaceutical Co., Ltd, lot number 100301.
Normal saline: Shandong Lukang Cisen Pharmaceutical Co., Ltd, lot number 1004234202.
Gamlogic acid: 10mg/ml, purity 98% (through hplc detection), lot number 20100819, had by Jiangsu Kang Yuan Pharmaceutical share
Limit company system is standby.
1.2 transplanted tumor
Human lung cancer nci-h460 Nude Mice, is inoculated in nude mouse by human lung cancer nci-h460 cell strain subcutaneous and build
Vertical.Cell inoculum concentration is 3 × 106, use after passing for 3 generations again in nude mice after inoculation formation transplanted tumor.
1.3 animal
Female balb/c nude mouse, age in days 35-40 days, body weight 18-22g, carried by zoopery section of hospital general of Nanjing Military Command
For.Every group of number of animals is negative control group 12, administration group 6.
1.4 test method
The tumor tissue taking growth animated period cuts into 1.5mm3Left and right, aseptically, is inoculated in axil on the right side of nude mouse
Nest is subcutaneous.Nude Mice vernier caliper measurement transplanted tumor diameter, treats tumour growth to 100～300mm3Afterwards by animal with
Machine is grouped.Using the method in measurement tumor footpath, dynamically observe the effect of tested drugs against tumor.The pendulous frequency of diameter of tumor is every
Week 3 times, measurement every time also needs to claim Mus weight simultaneously.Formula (1) compound intravenously administrable, dosage divides and is 12mg/kg, 6mg/
Kg, 3mg/kg, give three times weekly.Lid promise intravenously administrable 10mg/kg, gives weekly twice, each 0.2ml, and negative control group is simultaneously
To normal saline.
1.5 Testing index and computational methods
(1) gross tumor volume (tumor volume, tv), computing formula is:
Wherein a, b represent length and width respectively.
(2) relative tumour volume (relative tumor volnme, rtv), computing formula is:
rtv=tvt/ tv0
Wherein tv0For (d during sub-cage administration0) gross tumor volume, tvtFor gross tumor volume when measuring each time.
(3) Relative tumor rate of increase t/c (%), computing formula is:
T/c (%)=trtv/ crtv×100
trtv: treatment group rtv；crtv: negative control group rtv.
Result of the test is using Relative tumor rate of increase t/c (%) as the evaluation index of anti-tumor activity.
1.6 statistical method
Experimental data is represented with meansigma methodss and standard deviation, and statistical method adopts t- to check.
2. result
Formula (1) compound the results are shown in Table 2 to the experimental treatment of human lung cancer nci-h460.
Formula (1) compound high dose group intravenously administrable has preferable growth inhibited to human lung cancer nci-h460 mice-transplanted tumor
Effect, best t/c (%) is 61.97；
Middle dose group intravenously administrable 6mg/kg has certain growth inhibited to make human lung cancer nci-h460 Nude Mice
With best t/c (%) is 73.00；
Low dose group intravenously administrable 3mg/kg has certain growth inhibition effect to human lung cancer nci-h460 mice-transplanted tumor,
Preferably t/c (%) is respectively 75.59；
Lid promise intravenously administrable 10mg/kg has certain growth inhibition effect to human lung cancer nci-h460 Nude Mice,
Preferably t/c (%) is 56.69；
Gamlogic acid intravenously administrable 12mg/kg has certain growth inhibited to make human lung cancer nci-h460 Nude Mice
With best t/c (%) is 70.55.
The experimental therapy to human lung cancer nci-h460 Nude Mice for table 2 formula (1) compound
The rtv of d1 sub-cage administration time p administration group contrasts *: p < 0.05**:p < 0.01 with the rtv of blank group
The extracorporeal anti-tumor function of embodiment 4 the compounds of this invention
1. experiment material
1.1 cell strain
U251: human glioma cell's strain, purchased from Chinese Academy of Sciences's cell bank；
A549: human lung adenocarcinoma cell line, purchased from Chinese Academy of Sciences's cell bank；
Spc-a-1: human lung adenocarcinoma cell line, purchased from Chinese Academy of Sciences's cell bank；
Ho-8910: human oophoroma cell line, purchased from Chinese Academy of Sciences's cell bank.
1.2 tested materials and reagent
Formula (1) compound: purity 97%, lot number 20100121, are ground by Chinese Academy of Sciences's Shanghai medicine
Study carefully prepared；
0.25% trypsin-edta: gibco company of the U.S.；
Mtt solution: purchased from this hundred remittances bio tech ltd of Beijing；
Pbs buffer: Ji Nuo biological medicine technology company limited；
Dimethyl sulfoxide (dmso): analysis is pure.
1.3 experimental technique
1.3.1 Cell culture invitro
Cell is often restored to norm after reviving and is placed at 37 DEG C in incubator, 5%co2And cultivate under the conditions of saturated humidity, treat cell
When growing to exponential phase of growth, passed on 0.25% trypsin-dta digestion method.Absorb old culture fluid in bottle, washed away with pbs
Residual culture fluid, then add appropriate Digestive system (0.25% trypsin-edta) into bottle, make Digestive system submergence all cells table
Face, puts incubation in 37 DEG C of incubators (time is depending on different cells), puts and observed under microscope, find that kytoplasm bounces back, carefully
After intercellular space increases, the complete culture solution containing serum is added to terminate digestion immediately, centrifugation (1000rpm, 5min) removes supernatant afterwards
Liquid, with counting after culture fluid re-suspended cell, with cell number 3 × 105～5 × 105Cells/ml is seeded in new culture bottle, puts
Cultivated with above-mentioned condition of culture in incubator, 2～3d passes on once.
1.3.2mtt method detection
When cell growth is to exponential phase of growth, digested with 0.25% trypsin-dta, be centrifuged (1000rpm, 5min), carefully
Born of the same parents are precipitated and are adjusted cell number for 2 × 10 with complete medium4～3 × 104Cells/ml, 190 μ l are inoculated in the 96 hole culture every holes of version,
37 DEG C, 5%co2And cultivate under the conditions of saturated humidity, add formula (1) compound after 24h, make cumulative volume be 200 μ l, if 6 are multiple
Hole, control wells add pbs solution, continue culture 48h, add the mtt that 20 μ l concentration are 5mg/ml, are placed in co2Incubator 37
DEG C incubation, discards culture fluid after 4h, every hole adds 150 μ ldmso, vibrates 10min, put detection in enzyme micro-plate reader, measure each hole
Od value, calculate suppression ratio.The ic to subject cell strain for formula (1) compound50Weighted back by probit with spss15.0 software
Method is returned to calculate.
Suppression ratio computing formula:
2. experimental result
Experimental result shows (as table 3), and formula (1) compound all has inhibitory action, wherein people god to each tested tumor cell
Through the sensitivity highest to medicine for the glioma u251 cell strain.
The ic to each subject cell strain for table 3 formula (1) compound50(n=3)
The preparation of embodiment 5 tablet
According to the operational approach of conventional tablet, mixed above uniform, wet granulation, it is eventually adding magnesium stearate mix homogeneously
Tabletted, totally 50, every 500mg.
The preparation of embodiment 6 capsule
According to the operational approach of conventional capsule, mixed above uniform, wet granulation, fill becomes capsule, totally 90, every
300mg.
The preparation of embodiment 7 drop pill
The compounds of this invention 10.0g
Polyethylene glycol 6000 25.0g
The compounds of this invention is pulverized 100 mesh sieves, was uniformly added in molten polyethylene glycol 6000 substrate, stir 30
To uniform, with dimethicone 100 as coolant, 15-4 DEG C of gradient cools down minute, dripping pelletization, and centrifugation removes surface cooling
Agent, obtains final product drop pill 1000 ball.
The preparation of embodiment 8 powder ampoule agent for injection
The compounds of this invention 1.0g
Appropriate hydrochloric acid
Mannitol 50.0g
Operation according to conventional freeze-dried powder is carried out, and the compounds of this invention power 800ml water for injection dissolves, and adds manna
Alcohol, is settled to 1000ml, adjusts ph value to 5.0-6.5, aseptic filtration, and lyophilization obtains final product.
The preparation of embodiment 9 injection
The compounds of this invention is dissolved in dehydrated alcohol, adds 20% polyoxyl castor oil to mix, be evaporated under reduced pressure and remove
Ethanol, adds appropriate water for injection to be mixed into clear transparent solutions, through filtering with microporous membrane, coating-dividing sealing, flowing steam sterilization
Obtain final product.
The preparation of embodiment 10 slow releasing tablet
The compounds of this invention and polyvidone are dissolved in a small amount of ethanol, ethanol is evaporated under reduced pressure, 100 mesh sieves crossed by gained solid；
Above-mentioned solid and Lactose, Hypromellose are crossed 60 mesh sieves mix, add 3% hydroxypropyl methylcellulose (e5) appropriate aqueous solution
Soft material processed, crosses 20 mesh sieves and pelletizes, forced air drying.Dry particl crosses 20 mesh sieve granulate, adds the Pulvis Talci of recipe quantity, mixes, tabletting
Obtain final product.
The above is only the preferred embodiment of the present invention it is noted that ordinary skill people for the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of method of formula (1) compound, it comprises the steps of
(1) Resina garciniae medical material ethyl acetate is taken to extract, extract separates through silica gel column chromatography, petroleum ether-ethyl acetate gradient is washed
De-, obtain 11 component a～k；
(2) discard oil component and Resina garciniae acid constituents, through hplc-pda-ms analysis, obtain emphasis component i；
(3) component i separates through silica gel column chromatography again, chloroform-methanol gradient elution, and every 25～35ml collects a flow point, merges
11st part to the 16th part eluent, flow velocity is 2ml/min, obtains flow point i-3；
(4) take i-3 inverted rp-18 chromatographic isolation, acetonitrile-water gradient, every 15～25ml collects a flow point, merges the
13 parts to the 18th part eluents, flow velocity is 2ml/min, obtains Arius and divides i-3e；
(5) i-3e is purified, acetonitrile isocratic elution, obtains formula (1) compound.
2. method according to claim 1, wherein said step (1) petrochina ether-ethyl acetate 50～0:1 by volume
Ratio carry out gradient elution.
3. method according to claim 1, wherein said petroleum ether-ethyl acetate is divided into six gradients to carry out eluting, point
Not Wei 50:1,10:1,5:1,2:1,1:1,0:1.
4. method according to claim 1, the ratio of chloroform-methanol 50～10:1 by volume in wherein said step (3)
Example carries out gradient elution.
5. method according to claim 1, acetonitrile-water 40～90:60～10 by volume in wherein said step (4)
Ratio carries out gradient elution.
6. method as claimed in claim 5, wherein acetonitrile-water are divided into five gradients to carry out eluting, respectively 40:60,50:
50th, 60:40,80:20,90:10.
7. the method for claim 1, in wherein said step (5), the concentration of acetonitrile is 80%～95%.
8. method according to claim 7, the concentration of wherein said acetonitrile is 80%～85%.
9. method according to claim 8, the concentration of wherein said acetonitrile is 82%.
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