CN102488677B - Application of thelephora ganbajun in preparation of antitumor drugs - Google Patents
Application of thelephora ganbajun in preparation of antitumor drugs Download PDFInfo
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- CN102488677B CN102488677B CN 201110360944 CN201110360944A CN102488677B CN 102488677 B CN102488677 B CN 102488677B CN 201110360944 CN201110360944 CN 201110360944 CN 201110360944 A CN201110360944 A CN 201110360944A CN 102488677 B CN102488677 B CN 102488677B
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- VXVHENACWZPGBI-VDSCFQBISA-N C/C(/O)=C(\C=C(/C=C)\C(C(C(O)=C(c(cc1)ccc1O)C1=O)=O)=C1O)/O Chemical compound C/C(/O)=C(\C=C(/C=C)\C(C(C(O)=C(c(cc1)ccc1O)C1=O)=O)=C1O)/O VXVHENACWZPGBI-VDSCFQBISA-N 0.000 description 1
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Abstract
The invention belongs to the chemical field and the medical field, and relates to application of thelephora ganbajun in preparation of antitumor drugs. Tumor cells comprise hepatocellular carcinoma cells, lung adenocarcinma cells and pancreatic cancer cells. The thelephora ganbajun belongs to a natural product, is small in toxic and side effects, high in bioavailability and stable in performance, and has clinical service values. Small molecular compounds are developed as novel antitumor drugs or auxiliary elements of the novel antitumor drugs, are obvious in antitumor effect and are environment-friendly. The application of thelephora ganbajun in preparation of antitumor drugs provides a novel way and a novel means for treating and curing tumor.
Description
Technical field
The invention belongs to chemical field and field of medicaments, relate to the application of wizened rhzomorph in the preparation antitumor drug.
Background technology
GANBAJUN is the distinctive rare wild edible fungus in Yunnan Province, and other provinces of China reach abroad all can't grow.Formal name used at school: Sparassia crispa (Wulf.) Fr., also cry flower bacterium, gingival cyst of mucous gland in the newborn bacterium etc.It is grown between the mountain forest pinaster of the middle regions of the Yunnan Province and the western regions of the Yunnan Province, is top grade in the wild edible fungus.This bacterium does not have cap and lamella, clusters as the baurodont shape, is the baurodont hedgehog fungus so be commonly called as.When just being unearthed, this bacterium is yellowish-brown, become pitchy when aging and have generally to exactly like the strong fragrance that beefbacon is done because beefbacon do be called again wizened, the GANBAJUN so bacterium is gained the name.
GANBAJUN have very strong antibacterial activity, and it also is the important intermediate of synthetic potent immunosuppressant vialinin B simultaneously.Its structural formula is as follows:
1975, people such as Edwards have reported synthetic method (the Constituents of the higher fungi.XV.3-(3 of wizened rhzomorph (being the compound VI I in the literary composition), 4-Dihydroxyphenyl)-2,7,8-trihydroxydibenzofuran-1,4-dione, a precursor of thelephoric acid from the fungus Suillus grevillei[Boletus elegans] .Journal of the Chemical Society, Perkin Transactions 1:Organic and Bio-Organic Chemistry (1972-1999) (1975), (4), 351-4.).2009, Hu Lihong etc. have reported a kind of more simple and direct effectively method of synthetic wizened rhzomorph (being the leucomelone in the literary composition), and with the method for the synthesis of a series of 3,6-two replaces-2,5-dioxy benzoquinone skeleton compounds (An Approach to3,6-Disubstituted 2,5-Dioxybenzoquinones via Two Sequential Suzuki Couplings.Three-Step Synthesis of Leucomelone.Organic Letters (2009), 11 (3), 589-592.).
Yet, up to now, do not see as yet about wizened rhzomorph antineoplastic report.
Summary of the invention
The new medicinal usage that the purpose of this invention is to provide wizened rhzomorph.
The invention provides the application of wizened rhzomorph in the preparation antitumor drug.Described tumor can be hepatocarcinoma, adenocarcinoma of lung or cancer of pancreas.Described antitumor drug is injection or tablet.Described antitumor drug can be Antilung gland cancer medicine or anti-cancer of pancreas medicine.
The invention provides a kind of method that suppresses tumor cell in vitro propagation, wizened rhzomorph is added in the culture fluid of tumor cell.Described tumor cell is hepatoma carcinoma cell, lung adenocarcinoma cell or pancreatic cancer cell.The hepatoma carcinoma cell that adopts in one embodiment of the present of invention is HGC, and the pancreatic cancer cell of employing is PANC-1, and the lung adenocarcinoma cell of employing is A549.Generally speaking, the final concentration of the wizened rhzomorph of adding is 3-100 μ M.For example, 3-5 μ M, 3-10 μ M, 5-8 μ M, 5-10 μ M; Also have adopt heavy dose of, for example, 10-50 μ M, 5-60 μ M, etc.
The present invention also provides a kind of antitumor drug, and the active component of described antitumor drug is wizened rhzomorph.Described tumor can be hepatocarcinoma, adenocarcinoma of lung or cancer of pancreas.
Micromolecular compound of the present invention can adopt the preparation method preparation of various routines.For example, adopt the method for artificial chemosynthesis.
Utilize micromolecular compound of the present invention, by various conventional screening techniques, can filter out with wizened rhzomorph interactional material takes place, as receptor, inhibitor or antagonist etc.
The present invention and inhibitor, antagonist etc. when when (administration) used in treatment, can provide different effects.Usually, but these materials are formulated in nontoxic, inertia with pharmaceutically acceptable aqueous carrier medium in, wherein pH is about 5-8 usually, preferably pH is about 6-8, although pH value can change to some extent with being formulated Substance Properties and disease to be treated.The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
Be example with wizened rhzomorph of the present invention, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains chemical compound and pharmaceutically acceptable carrier or the excipient for the treatment of effective dose.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.Wizened rhzomorph of the present invention can be made into the injection form, for example is prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of active component is the treatment effective dose, for example every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, wizened rhzomorph of the present invention also can use with the other treatment agent.
When wizened rhzomorph of the present invention is used as medicine, the wizened rhzomorph for the treatment of effective dose can be applied to mammal, wherein should treat effective dose usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
The invention provides the application of wizened rhzomorph in the preparation antitumor drug.Wizened rhzomorph is natural product, can obviously suppress the propagation of tumor cell.Micromolecular compound of the present invention is developed as new antitumor drug or its auxiliary element, and tumor killing effect is obvious, environmental protection, and will and cure tumor for treatment provides a kind of new approach and means.
The specific embodiment
Experimental technique:
1. cell recovery
1) from liquid nitrogen container, takes out frozen pipe, directly drop in 37 ℃ of warm water, and shake frequently and make it melt as early as possible.
2) from 37 ℃ of water-baths, take out frozen pipe, with suction pipe sucking-off cell suspension, inject centrifuge tube and add culture fluid more than 10 times, mix the back low-speed centrifugal, abandon supernatant, repeat again to wash once with culture fluid.
3) with after the suitable dilution of culture fluid, the inoculated and cultured bottle is placed on 37 ℃ of incubators and leaves standstill cultivation, changes culture fluid next day, continues to cultivate.Go down to posterity when being cultured to finite concentration.The PANC-1 cell culture is in containing the DMEM high glucose medium of 10%Gibico hyclone, and the HGC cell culture contains 100U/ml penicillin and 100 μ g/ml streptomycins in the culture medium in containing 1640 culture medium of 10% hyclone.
2. passage is cultivated
The situation of observation of cell growth every day goes down to posterity when converging (attached cell) when cell grows to about 90% in culture bottle, goes down to posterity once every 2-4 days approximately.One bottle goes down to posterity into three bottles, or a 25cm
2Go down to posterity in a 75cm
2Culture bottle in.Method:
1) with 1 * phosphate buffer washed cell once.
2) add the digestion of 2-3ml trypsinization liquid, place 37 ℃ of incubator numbers minute.Pat Tissue Culture Flask with hands, make cell separation.
3) suitable culture medium with the Gibico hyclone that contains 10-15% stops trypsinization.Cell is sub-packed in the new culture bottle, continues to cultivate.
3. cell cryopreservation
1) get the cell tryptase protease digestion that is cultured to exponential phase, be collected in the centrifuge tube and counting, centrifugal.
2) reject trypsin and old culture fluid add the frozen culture fluid (containing 10%DMSO, 40%DMEM and 50%Gibico hyclone) that configures, and the ultimate density of cell is 0.5-1 * 10 in the cryopreserving liquid
7/ ml.Blow and beat gently with suction pipe and to make cell even, divide in the aseptic frozen pipe of packing into then, every pipe adds 1-1.5ml.
3) frozen pipe is put into freezing storing box and put-80 ℃ of quick-freezings, move in the liquid nitrogen container after 5 hours and preserve.
Embodiment 1 MTS method is measured wizened rhzomorph to the growth inhibited effect of hepatoma carcinoma cell
HGC cell (available from Chinese Academy of Sciences's cell bank) 3 * 10
3/ hole is seeded to 96 orifice plates, cultivates to make it the wizened rhzomorph (available from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences) of adherent back adding in 24 hours, establishes 6 Concentraton gradient, and each concentration is established 3 multiple holes.Cell is at 37 ℃, 5%CO
2Cultivate after 72 hours under the condition, outwell culture fluid, measure cell survival rate with MTS test kit (Promega company).
Method of testing is: cell is washed one time with serum-free medium, added the MTS chromophoric solution (adding 2ml solution 1 and 100 μ l solution 2 in the 10ml serum-free medium, fully mixings) for preparing in advance according to the amount of 100 μ l/well.Do not have the hole of cell to be made as this bottom outlet with one, absorb in order to the bias light of calibration solution.Cell is put into cell culture incubator to be continued to cultivate 2～4 hours, read absorbance value (reference wavelength 630-700nm with microplate reader then, measure wavelength 490nm), calculate cell survival rate, to measure hole absorbance value/control wells absorbance value as the numerical value of cell survival rate.According to cell survival rate, calculate wizened rhzomorph to the IC50 value of HGC cell.
IC50 refers to be suppressed the concentration of a half inhibitor.Here be the HGC cell quantity and be the concentration of a half GANBAJUN element of contrast.The calculating of IC50 generally need be measured the dosage effect more than 5, obtains function calculation by curve fitting again and gets.
The result: wizened rhzomorph is 430 μ M to the IC50 value of HGC cell.
Embodiment 2 wizened rhzomorphs are to the growth inhibited effect of human pancreatic cancer cell
Utilize cck-8 test kit (Japanese colleague's chemistry institute) to detect.
Step:
1) PANC-1 cell (available from ATCC) is planted in 96 orifice plates uniformly, every porocyte number is 3000.
2) treat adherent, spend the night the back dosing.
3) cultivate 48 hours, complete medium is replaced to the mixture (10: 1) of serum-free medium and CCK8, hatched 2 hours in 37 ℃ of incubators.
4) being to measure wavelength with 450nm, is the contrast wavelength with 650nm, measures reading on microplate reader.
The result: wizened rhzomorph is 3.29 μ M to the IC50 value of PANC-1 cell.
Embodiment 3 wizened rhzomorphs are to the growth inhibited effect of human lung adenocarcinoma cell
With the method for embodiment 2, recording wizened rhzomorph is 8.54 μ M to the IC50 value of A549 cell.
Claims (7)
1. the application of the wizened rhzomorph of following structural formula in the preparation antitumor drug, described tumor is hepatocarcinoma, cancer of pancreas or adenocarcinoma of lung;
2. application as claimed in claim 1 is characterized in that, described antitumor drug is medicines resistant to liver cancer.
3. application as claimed in claim 1 is characterized in that, described antitumor drug is anti-cancer of pancreas medicine.
4. application as claimed in claim 1 is characterized in that, described antitumor drug is Antilung gland cancer medicine.
5. a method that suppresses tumor cell in vitro propagation is characterized in that, the wizened rhzomorph of following structural formula is added in the culture fluid of tumor cell; Described tumor cell is hepatoma carcinoma cell, pancreatic cancer cell or lung adenocarcinoma cell;
6. method as claimed in claim 5 is characterized in that, the final concentration that adds wizened rhzomorph is 3-100 μ M.
7. an antitumor drug is characterized in that, the active component of described antitumor drug is the wizened rhzomorph of following structural formula; Described antitumor drug is medicines resistant to liver cancer, anti-cancer of pancreas medicine or Antilung gland cancer medicine;
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201110360944 CN102488677B (en) | 2011-11-15 | 2011-11-15 | Application of thelephora ganbajun in preparation of antitumor drugs |
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| CN 201110360944 CN102488677B (en) | 2011-11-15 | 2011-11-15 | Application of thelephora ganbajun in preparation of antitumor drugs |
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| CN102488677A CN102488677A (en) | 2012-06-13 |
| CN102488677B true CN102488677B (en) | 2013-08-21 |
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| CN112843101B (en) * | 2019-11-26 | 2022-07-29 | 北京大学 | Application of Thelephora ganbajun zang in protecting liver injury |
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Non-Patent Citations (3)
| Title |
|---|
| an approach to 3,6-disubstituted 2,5-dioxybenzoquinones via two sequential suzuki couplings. three-step synthesis of leucomelone;Xianwen Gan, et al.;《organic letters》;20090108;第11卷(第3期);第589-592页 * |
| XianwenGan et al..an approach to 3 |
| 图力古尔，等.大型真菌色素的研究现状与应用前景.《菌物研究》.2005,第3卷(第4期),第57-62页. * |
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