CN103083331A - Application of solanum laciniatum ketene in preparing antitumor medicines - Google Patents
Application of solanum laciniatum ketene in preparing antitumor medicines Download PDFInfo
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- CN103083331A CN103083331A CN201110340486XA CN201110340486A CN103083331A CN 103083331 A CN103083331 A CN 103083331A CN 201110340486X A CN201110340486X A CN 201110340486XA CN 201110340486 A CN201110340486 A CN 201110340486A CN 103083331 A CN103083331 A CN 103083331A
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Abstract
The invention belongs to the fields of chemical engineering and medicines, and relates to the application of solanum laciniatum ketene in preparing antitumor medicines. The invention provides the application of solanum laciniatum ketene in preparing antitumor medicines. The tumor cells comprise liver cancer cells, blood cancer cells, cervical cancer cells, breast cancer cells, and pancreatic cancer cells. Solanum laciniatum ketene is a natural product with low toxic and side effect, high bioavailability, stable quality, and clinical application values. The small-molecular compound provided by the invention is developed as a novel antitumor medicine or an auxiliary component thereof. A tumor inhibiting effect is substantial, and the compound is green and environment-friendly. Therefore, novel approach and means are provided for treating and curing tumors.
Description
Technical field
The invention belongs to chemical field and field of medicaments, relate to the application of Australian eggplant ketenes in the preparation antitumor drug.
Background technology
(E) methyl-3-[2-(4-hydroxy 3-methoxybenzene base)-3-methylol-7-methoxyl group-2,3-dihydro-1-benzofuran-5-yl]-alkynes-2-olefin(e) acid ethyl ester (methyl (E)-3-[2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-2,3-dihydro-1-benzofuran-5-yl]-prop-2-enoate) (lower be called for short Australian eggplant ketenes) be the derivant of solasodine.The structure of Australian eggplant ketenes is as follows:
Report (Compound I, Study of the Wolff-Kishnerreaction in a series of solasodine steroid alkaloid derivatives.Irismetov, M.P. that chemical preparation was just arranged as far back as the seventies in last century; Goryaev, M.I.; Kuril ' skaya, V.V.Inst.Khim.Nauk, Alma-Ata, USSR.IzvestiyaAkademii Nauk Kazakhskoi SSR, Seriya Khimicheskaya (1979), (3), 58-60.).
The Australian eggplant ketenes belongs to natural product, and effect (Compound I, New steroidconstituents of the Vietnamese Solanaceae Solanum hainanense Hance.Adam, the G. of certain inhibition bacillus subtilis arranged; Huong, H.T.; Lischewski, M.; Khoi, N.H.Inst.Biochem.Pflanzen, DAW, Halle/Saale, Ger.Dem.Rep.Pharmazie, 1979), certain antifungic action (Antifungal stress metabolites fromSolanum aviculare.Rowan, Daryl D. are also arranged; MacDonald, Paul ine E.; Skipp, Robert A.Appl.Biochem.Div., DSIR, Palmerston, N.Z.Phytochemistry, 1983,22 (9), 2102-4.).The Australian eggplant ketenes still prepares one of raw material of Alfasone progesterone (Degradation of the steroidal alkaloidsolasodenone to progesterone.Adam, Guenter; Hoang Thanh Huong; Lischewski, Manfred.Inst.Biochem.Pflanz.Weinberg, Dtsch.Akad.Wiss., Halle/Saale, Ger.Dem.Rep.Zeitschrift fuer Chemie.(1986)，26(10)，369.)。
Australian eggplant ketenes toxic and side effects is little, bioavailability is high, stable in properties, has clinical use value.To going deep into that this type of alkaloidal chemistry and biology is studied, its molecular mechanism of action will be progressively clear and definite along with people, and this chemical constitution that will further promote this compounds is modified and structure activity study, and helps to improve the medical value of this compounds.
Summary of the invention
The medicinal usage that the purpose of this invention is to provide the Australian eggplant ketenes.
The invention provides the application of Australian eggplant ketenes in the preparation antitumor drug.Described antitumor drug can be medicines resistant to liver cancer or anti-leukemia medicine.This antitumor drug can be injection or tablet.
The invention provides a kind of method that suppresses tumor cell in vitro propagation, the Australian eggplant ketenes is added in the culture fluid of tumor cell.Described tumor cell can be hepatoma carcinoma cell, blood cell, cervical cancer cell, breast cancer cell or pancreatic cancer cell.The hepatoma carcinoma cell that adopts in one embodiment of the present of invention is SK-HEP1, Focus and QGY.Generally speaking, adding the final concentration of Australian eggplant ketenes is 2-100 μ M.For example, 2-5 μ M, 2-10 μ M, 2-12 μ M, 2-20 μ M, 2-30 μ M, 2-60 μ M, 40-90 μ M, 60-80 μ M, 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 the Australian eggplant ketenes.Described tumor can be hepatocarcinoma or leukemia.
Micromolecular compound of the present invention 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 the interactional material of Australian eggplant ketenes generation, as receptor, inhibitor or antagonist etc.
The present invention and inhibitor, antagonist etc. when using (administration) 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 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 Australian eggplant ketenes 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.Australian eggplant ketenes 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, Australian eggplant ketenes of the present invention also can use together with the other treatment agent.
When Australian eggplant ketenes of the present invention is used as medicine, the Australian eggplant ketenes 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 Australian eggplant ketenes in the preparation antitumor drug.The Australian eggplant ketenes 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 containing the DMEM high glucose medium of 10%Gibico hyclone, and SK-HEP1 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 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.
4. medicine is prepared:
The Australian eggplant ketenes is dissolved in DMSO (dimethyl sulfoxide), is mixed with 1,10,100 μ M standby.
Embodiment 1MTS method is measured the Australian eggplant ketenes to the growth inhibited effect of hepatoma carcinoma cell
SK-HEP1 cell (available from Chinese Academy of Sciences's cell bank) 3 * 10
3/ hole is seeded to 96 orifice plates, cultivates to make it in 24 hours to add Australian eggplant ketenes (available from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences) 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 the Australian eggplant ketenes to the IC50 value of Sk-hep1 cell.
IC50 refers to the concentration of a suppressed half inhibitor.Here be the SK-HEP1 cell quantity and be the concentration of a half Australian eggplant ketenes 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: the Australian eggplant ketenes is 61.8 μ M to the IC50 value of Sk-hep1 cell.
The test QGY cell (available from Chinese Academy of Sciences's cell bank) that uses the same method, the Australian eggplant ketenes is about 89.8 μ M to the IC50 value of QGY cell as a result; Being about 59.9 μ M to the IC50 value of Focus cell, is about 910 μ M to the IC50 value of hep-G2 cell.
The growth inhibited effect of embodiment 2 Australian eggplant ketenes to human pancreatic cancer cell
Utilize cck-8 test kit (Japanese colleague's chemistry institute) to detect.
Step:
1) K562 cell (available from Chinese Academy of Sciences's cell bank) is planted in 96 orifice plates uniformly, every porocyte number is 10
4Individual.
2) treat adherent, the rear dosing of spending the night, (Australian eggplant ketenes 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: the Australian eggplant ketenes is 2.63 μ M to the IC50 value of K562 cell.
Claims (10)
1. the application of Australian eggplant ketenes in the preparation antitumor drug.
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-leukemia medicine.
4. application as claimed in claim 1, is characterized in that, this antitumor drug is injection or tablet.
5. a method that suppresses tumor cell in vitro propagation, is characterized in that, the Australian eggplant ketenes added in the culture fluid of tumor cell.
6. method as claimed in claim 5, is characterized in that, described tumor cell is hepatoma carcinoma cell or blood cell.
7. method as claimed in claim 6, is characterized in that, described hepatoma carcinoma cell is Sk-hep1, Focus or QGY.
8. method as claimed in claim 5, is characterized in that, the final concentration that adds the Australian eggplant ketenes is 2-100 μ M.
9. an antitumor drug, is characterized in that, the active component of described antitumor drug is the Australian eggplant ketenes.
10. antitumor drug as claimed in claim 9, is characterized in that, described tumor is hepatocarcinoma.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417527A (en) * | 2012-05-21 | 2013-12-04 | 复旦大学 | Medical uses of methyl (E)-3-[2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-2,3-dihydro-1-benzofuran-5-yl]-prop-2-enoate |
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2011
- 2011-11-01 CN CN201110340486.XA patent/CN103083331B/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| HANG-JI QUAN，ET AL: "《Preparations of heterospirostanols and their pharmacological activities", 《EUR. J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103417527A (en) * | 2012-05-21 | 2013-12-04 | 复旦大学 | Medical uses of methyl (E)-3-[2-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-2,3-dihydro-1-benzofuran-5-yl]-prop-2-enoate |
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