CN103127049A - Application of usnic acid in manufacturing antitumor drugs - Google Patents
Application of usnic acid in manufacturing antitumor drugs Download PDFInfo
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- CN103127049A CN103127049A CN2011103835409A CN201110383540A CN103127049A CN 103127049 A CN103127049 A CN 103127049A CN 2011103835409 A CN2011103835409 A CN 2011103835409A CN 201110383540 A CN201110383540 A CN 201110383540A CN 103127049 A CN103127049 A CN 103127049A
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Abstract
The invention belongs to the field of chemical industry and medicine and relates to application of usnic acid in manufacturing antineoplastic drug. A cancer cell comprises leukemia cell, liver cancer cell and lung adenocarcinoma cell. The usnic acid belongs to a natural product so that bioavailability is high and quality is stable, and the usnic acid has clinical used value. A small molecule compound is regarded as a new antineoplastic drug or an auxiliary element to develop. The usnic acid has the advantages of being obvious in anti-tumor effect, environment-friendly and providing a new method and way to treat and heal tumor.
Description
Technical field
The invention belongs to chemical field and field of medicaments, relate to the application of usnic acid in the preparation antitumor drug.
Background technology
Usnic acid, another name: lichenic acid.Plant origin: the dry thallus of Usneaceae (Usneaceae) plant Usnea Usnea diffractaVain. and Usnea Longissima Usnea longissima Ach..
Character: yellow tiltedly quadratic prism shape crystallization (acetone).204 ℃ of fusing points.Optical rotation+509.4 ° (c=0.697, chloroform).Dissolubility in the time of 25 ℃ (g/100ml water)＜0.01, acetone 0.77, ethyl acetate 0.88, ethanol 0.02, alditol 7.32, sugar alcohol 1.21.But chemosynthesis or biosynthesis make.
CAS：125-46-2
Molecular formula: C18H1607
Molecular weight: 344.32
Another name: usnic acid; (+)-Usnic acid; (+)-Usnein; (+)-Usniacin;
D-2，6-Diacetyl-7，9-dihydroxy-8，9b-dimethyl-1，3(2H，9bH)-Dibenzofurandione；
Structural formula:
Character: yellow crystal powder.
Fusing point: 192-204 ℃
Optical rotation: [α] D20+495 °～497 ° (C=1, in CHC13)
Stability: generally stable.
This product is a kind of broad ectrum antibiotic, and most gram-positive bacteriums are had powerful inhibitory action, also can suppress the growth of tulase.If share with a small amount of streptomycin, its interaction energy that suppresses tulase is strengthened greatly, and toxicity is very little.Usnic acid also has inhibitory action to protozoon, trichomonas vaginitis.Rat feeding usnic acid to partially hepatectomized has the effect that promotes liver regeneration.
Clinically malaria there is certain curative effect.Wound, burn and dermatosis, cervicitis, nipple Fissure, prevention perineal rupture etc. there is certain curative effect.Lichenic acid comes from natural Usnea.For hemostasis, antibiotic, antiinflammatory, wound healing except dental plaque, strengthens body immunity, and the routed disease in oral cavity and vaginitis are had curative effect preferably.The additive of Chang Zuowei toothpaste and cosmetics.
In addition, usnic acid also can be used as the raw material of antibiotics " the pyrrole food in one's mouth ".
Summary of the invention
The new medicinal usage that the purpose of this invention is to provide usnic acid.
The invention provides the application of usnic acid in the preparation antitumor drug.Described tumor can be hepatocarcinoma, leukemia or adenocarcinoma of lung.Described antitumor drug is injection or tablet.Described antitumor drug can be leukemia or adenocarcinoma of lung medicine.
The invention provides a kind of method that suppresses tumor cell in vitro propagation, usnic acid is added in the culture fluid of tumor cell.Described tumor cell is hepatoma carcinoma cell, leukaemia or lung adenocarcinoma cell.Generally speaking, adding the final concentration of usnic acid is 0.5-60 μ M.For example, 0.5-5 μ M, 0.5-6 μ M, 0.5-20 μ M, 0.5-60 μ M, 5-50 μ M, 5-60 μ M, 1-50 μ M, 5-30 μ M, 5-20 μ M, 5-10 μ M, 1-60 μ M, etc.
The present invention also provides a kind of antitumor drug, and the active component of described antitumor drug is usnic acid.Described tumor can be hepatocarcinoma, leukemia, adenocarcinoma of lung, etc.
Micromolecular compound of the present invention can obtain by buying from market, also can adopt the preparation method preparation of various routines.For example, adopt the synthetic method of artificial chemistry.
Utilize micromolecular compound of the present invention, by various conventional screening techniques, can filter out and interactional material occurs usnic acid, as receptor, inhibitor or pick up anti-dose etc.
The present invention and inhibitor thereof, pick up anti-dose etc., when using (administration) in treatment, can provide different effects.Usually, these materials can be formulated in nontoxic, inertia with pharmaceutically acceptable aqueous carrier medium in, wherein pH is about 5-8 usually, preferably pH is about 6-8, pH value can change to some extent with the character that is formulated material 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.
Take usnic acid of the present invention as example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains 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.Usnic acid 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 Capsula can be prepared by conventional method.Pharmaceutical composition such as injection, solution, Tablet and Capsula should be made under aseptic condition.The dosage of active component is the treatment effective dose, for example every day about 5 mg/kg body weight of 1 microgram/kg body weight-Yue.In addition, usnic acid of the present invention also can use together with the other treatment agent.
When usnic acid of the present invention is used as medicine, the usnic acid 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 approximately 8 mg/kg body weight, preferably this dosage is the about 1 mg/kg body weight of 10 micrograms/kg body weight-Yue.Certainly, concrete dosage also should be considered the factors such as route of administration, patient health situation, and these are all within the skilled practitioners skill.
The invention provides the application of usnic acid in the preparation antitumor drug.Usnic acid is natural product, obviously the propagation of inhibition 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) take out cryopreservation tube from liquid nitrogen container, directly drop in 37 ℃ of warm water, and frequently shake and make it melt as early as possible.
2) take out cryopreservation tube from 37 ℃ of water-baths, with suction pipe sucking-off cell suspension, inject centrifuge tube and add culture fluid more than 10 times, low-speed centrifugal after mixing is abandoned supernatant, then is repeated 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 standing cultivations of incubator, 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 the DMEM high glucose medium that contains 10% Gibico hyclone, and SMMC-7721 and QGY cell culture contain 100U/ml penicillin and 100 μ g/ml streptomycins in culture medium in containing the DMEM high glucose medium of 10% hyclone.
2. passage is cultivated
The situation of observation of cell growth every day is grown to approximately 90% and is gone down to posterity when converging (attached cell) in culture bottle when cell, approximately went down to posterity once every 2-4 days.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 2-3ml trypsinization liquid digestion, be placed in 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 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 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 in cryopreserving liquid, the ultimate density of cell is 0.5-1 * 10
7/ ml.Blow and beat gently with suction pipe and make cell even, then be distributed in aseptic cryopreservation tube, every pipe adds 1-1.5ml.
3) cryopreservation tube is put into freezing storing box and put-80 ℃ of quick-freezings, move in liquid nitrogen container after 5 hours and preserve.
The growth inhibited effect of embodiment 1 usnic acid to human liver cancer cell
HepG2 cell (available from ATCC) 1 * 10
3/ hole is seeded to 96 orifice plates, cultivates to make it in 24 hours to add usnic acid after adherent, establishes 6 Concentraton gradient, and each concentration is established 3 multiple holes.Cell is at 37 ℃, 5%CO
2Cultivate after 72 hours under 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 mixing) 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, then read absorbance value (reference wavelength 630-700nm with microplate reader, 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 usnic acid to the IC50 value of HepG2 cell.
IC50 refers to a suppressed half
InhibitorConcentration.Here be the HepG2 cell quantity and be the concentration of a half usnic acid of contrast.The calculating of IC50 generally need to be measured the dosage effect more than 5, then obtains function calculation by curve fitting and get.
Result: usnic acid is 0.64 μ M to the IC50 value of HepG2 cell.
The growth inhibited effect of embodiment 2 usnic acids to human lung adenocarcinoma cell
Utilize cck-8 test kit (Japanese colleague's chemistry institute) to detect.
Step:
1) A549 cell (available from Chinese Academy of Sciences's cell bank) is planted in 96 orifice plates uniformly, every porocyte number is 3000.
2) treat adherent, the rear dosing of spending the night, (usnic acid concentration is respectively 50,16.67,5.56,1.85,0.62 μ M, and each concentration has 3 multiple holes in dosing.
3) cultivated 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) take 450nm as measuring wavelength, take 650nm as the contrast wavelength, measure reading on microplate reader.
Result: usnic acid is 58.56 μ M to the IC50 value of A549 cell.
The growth inhibited effect of embodiment 3 usnic acids to the human leukemia cell
Detect usnic acid to the growth inhibited effect of K562 cell according to the method for embodiment 2, usnic acid is 5.12 μ M to the IC50 value of K562 cell as a result.
Claims (10)
1. the application of usnic acid in the preparation antitumor drug.
2. application as claimed in claim 1, is characterized in that, described tumor is leukemia, hepatocarcinoma or adenocarcinoma of lung.
3. application as claimed in claim 1, is characterized in that, described antitumor drug is anti-leukemia medicine.
4. application as claimed in claim 1, is characterized in that, described antitumor drug is Antilung gland cancer medicine.
5. application as claimed in claim 1, is characterized in that, the dosage form of described antitumor drug is injection, tablet or capsule.
6. a method that suppresses tumor cell in vitro propagation, is characterized in that, usnic acid added in the culture fluid of tumor cell.
7. method as claimed in claim 6, is characterized in that, described tumor cell is leukemia, hepatocarcinoma or lung adenocarcinoma cell.
8. method as claimed in claim 6, is characterized in that, the final concentration that adds usnic acid is 0.5-60 μ M.
9. an antitumor drug, is characterized in that, the active component of described antitumor drug is usnic acid.
10. antitumor drug as claimed in claim 9, is characterized in that, described tumor is leukemia, hepatocarcinoma or adenocarcinoma of lung.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103835409A CN103127049A (en) | 2011-11-25 | 2011-11-25 | Application of usnic acid in manufacturing antitumor drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103835409A CN103127049A (en) | 2011-11-25 | 2011-11-25 | Application of usnic acid in manufacturing antitumor drugs |
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| CN103127049A true CN103127049A (en) | 2013-06-05 |
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| CN2011103835409A Pending CN103127049A (en) | 2011-11-25 | 2011-11-25 | Application of usnic acid in manufacturing antitumor drugs |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581008A (en) * | 2016-12-23 | 2017-04-26 | 郑州仁宏医药科技有限公司 | Drug for treating leukemia, and preparation method and application thereof |
| CN107149600A (en) * | 2016-03-03 | 2017-09-12 | 北京中医药大学 | The purposes of dibenzofurans compound |
| CN110734429A (en) * | 2019-11-22 | 2020-01-31 | 昆明医科大学 | Usnea nicotinamide compound and preparation method and application thereof |
| CN111393278A (en) * | 2020-04-20 | 2020-07-10 | 山西白求恩医院(山西医学科学院) | Usnea longissima derivative and application thereof in preparation of medicine for treating gallbladder cancer |
| CN114984068A (en) * | 2022-05-31 | 2022-09-02 | 袁忠开 | Use of lichen for treating cancer |
-
2011
- 2011-11-25 CN CN2011103835409A patent/CN103127049A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| A.T. KOPARALA ET AL: "In vitro cytotoxic activities of (+)-usnic acid and (-)-usnic acid on V79, A549, and human lymphocyte cells and their non-genotoxicity on human lymphocytes", 《NATURAL PRODUCT RESEARCH》 * |
| M.CARDARELLI ET AL.: "Antimitotic effects of usnic acid on different biological systems", 《CELLULAR AND MOLECULAR LIFE SCIENCES》 * |
| SAURA C. SAHU ET AL.: "Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture.", 《JOURNAL OF APPLIED TOXICOLOGY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107149600A (en) * | 2016-03-03 | 2017-09-12 | 北京中医药大学 | The purposes of dibenzofurans compound |
| CN106581008A (en) * | 2016-12-23 | 2017-04-26 | 郑州仁宏医药科技有限公司 | Drug for treating leukemia, and preparation method and application thereof |
| CN110734429A (en) * | 2019-11-22 | 2020-01-31 | 昆明医科大学 | Usnea nicotinamide compound and preparation method and application thereof |
| CN110734429B (en) * | 2019-11-22 | 2022-05-03 | 昆明医科大学 | Usnea nicotinamide compound and preparation method and application thereof |
| CN111393278A (en) * | 2020-04-20 | 2020-07-10 | 山西白求恩医院(山西医学科学院) | Usnea longissima derivative and application thereof in preparation of medicine for treating gallbladder cancer |
| CN114984068A (en) * | 2022-05-31 | 2022-09-02 | 袁忠开 | Use of lichen for treating cancer |
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Application publication date: 20130605 |