CN103083331B - 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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- CN103083331B CN103083331B CN201110340486.XA CN201110340486A CN103083331B CN 103083331 B CN103083331 B CN 103083331B CN 201110340486 A CN201110340486 A CN 201110340486A CN 103083331 B CN103083331 B CN 103083331B
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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 Australian eggplant ketenes and preparing the application in antitumor drug.
Background technology
(E) methyl-3-[2-(4-hydroxy 3-methoxybenzene base)-3-methylol-7-methoxyl group-2,3-dihydro-1-benzofuran-5-base]-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) is 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, the M.P. of chemical preparation is just had 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.).
Australian eggplant ketenes belongs to natural product, has effect (Compound I, New steroidconstituents of the Vietnamese Solanaceae Solanum hainanense Hance.Adam, the G. of certain suppression bacillus subtilis; Huong, H.T.; Lischewski, M.; Khoi, N.H.Inst.Biochem.Pflanzen, DAW, Halle/Saale, Ger.Dem.Rep.Pharmazie, 1979), also certain antifungic action (Antifungal stress metabolites fromSolanum aviculare.Rowan, Daryl D. is had; MacDonald, Paul ine E.; Skipp, Robert A.Appl.Biochem.Div., DSIR, Palmerston, N.Z.Phytochemistry, 1983,22 (9), 2102-4.).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 practice and is worth.Along with people's going deep into this type of alkaloidal chemistry and biology research, its molecular mechanism of action will be progressively clear and definite, and this will promote modifying for chemical structure and the structure activity study of this compounds further, and contribute to the medical value improving this compounds.
Summary of the invention
The object of this invention is to provide the medicinal usage of Australian eggplant ketenes.
The invention provides Australian eggplant ketenes and prepare the application in 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 suppressing tumor cell in vitro to be bred, 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 adopted in one embodiment of the present of invention is SK-HEP1, Focus and QGY.Generally speaking, the final concentration adding Australian eggplant ketenes is 2-100 μM.Such as, 2-5 μM, 2-10 μM, 2-12 μM, 2-20 μM, 2-30 μM, 2-60 μM, 40-90 μM, 60-80 μM, 10-50 μM, 5-60 μM, etc.
Present invention also offers a kind of antitumor drug, the active component of described antitumor drug is Australian eggplant ketenes.Described tumor can be hepatocarcinoma or leukemia.
Micromolecular compound of the present invention can adopt the preparation method of various routine to prepare.Such as, the method for artificial chemistry synthesis is adopted.
Utilize micromolecular compound of the present invention, by various conventional screening assays, can filter out and with Australian eggplant ketenes, interactional material occur, as receptor, inhibitor or antagonist etc.
The present invention and inhibitor, antagonist etc., when carrying out using (administration) on treating, can provide different effects.Usually, but these materials are formulated in nontoxic, inertia with in pharmaceutically acceptable aqueous carrier medium, wherein pH is about 5-8 usually, and preferably pH is about 6-8, although pH value can with being formulated the character of material and disease to be treated and changing to some extent.The pharmaceutical composition prepared can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
For Australian eggplant ketenes of the present invention, can by itself and suitable pharmaceutically acceptable carrier coupling.This kind of pharmaceutical composition contains the compound and pharmaceutically acceptable carrier or excipient for the treatment of effective dose.This kind of carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should match with administering mode.Australian eggplant ketenes of the present invention can be made into injection form, such as, be prepared by conventional method with normal saline or the aqueous solution containing glucose and other adjuvant.The pharmaceutical composition of such as Tablet and Capsula and so on, is prepared by conventional method.Pharmaceutical composition such as injection, solution, Tablet and Capsula should aseptically manufacture.The dosage of active component is treatment effective dose, such as every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, Australian eggplant ketenes of the present invention also can use together with 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 this treatment effective dose is usually at least about 10 micrograms/kg body weight, and be in most of the cases 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 consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
The invention provides Australian eggplant ketenes and prepare the application in antitumor drug.Australian eggplant ketenes is natural product, can the propagation of obvious 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, provides a kind of new approach and means by for treatment and healing tumor.
Detailed description of the invention
Experimental technique:
1. cell recovery
1) from liquid nitrogen container, take out cryopreservation tube, directly drop in 37 DEG C of warm water, and shake makes it melt as early as possible frequently.
2) from 37 DEG C of water-baths, take out cryopreservation tube, with suction pipe sucking-off cell suspension, inject centrifuge tube and add more than 10 times culture fluid, low-speed centrifugal after mixing, abandons supernatant, then repeats to wash once with culture fluid.
3), after suitably diluting with culture fluid, inoculated and cultured bottle, be placed on 37 DEG C of incubator quiescent culture, next day changes culture fluid, continues to cultivate.Go down to posterity when being cultured to finite concentration.PANC-1 cell culture is in the DMEM high glucose medium containing 10%Gibico hyclone, SK-HEP1 and QGY cell culture, containing in the DMEM high glucose medium of 10% hyclone, contains 100U/ml penicillin and 100 μ g/ml streptomycins in culture medium.
2. passage is cultivated
Every day observation of cell growth situation, when cell grow in culture bottle about 90% converge time go down to posterity, about 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 the digestion of 2-3ml trypsinization liquid, be placed in 37 DEG C of incubator numbers minute.Pat Tissue Culture Flask with hands, make cell separation.
3) trypsinization is stopped with the suitable culture medium of the Gibico hyclone containing 10-15%.Cell is sub-packed in new culture bottle, continues to cultivate.
3. cell cryopreservation
1) get the cell tryptase protease digestion being cultured to exponential phase, to be collected in centrifuge tube and to count, centrifugal.
2) reject trypsin and old culture fluid, add the frozen culture fluid (containing 10%DMSO, 40%DMEM and 50%Gibico hyclone) configured, in cryopreserving liquid, the ultimate density of cell is 0.5-1 × 10
7/ ml.Blowing and beating gently with suction pipe makes cell even, and be then distributed in aseptic cryopreservation tube, often pipe adds 1-1.5ml.
3) cryopreservation tube is put into freezing storing box and put-80 DEG C of quick-freezings, move in liquid nitrogen container after 5 hours and preserve.
4. medicine prepares:
Australian eggplant ketenes is dissolved in DMSO (dimethyl sulfoxide), be mixed with 1,10,100 μM for subsequent use.
Embodiment 1MTS method measures Australian eggplant ketenes to the growth inhibited effect of hepatoma carcinoma cell
SK-HEP1 cell (purchased from Chinese Academy of Sciences's cell bank) 3 × 10
3/ hole is seeded to 96 orifice plates, cultivate within 24 hours, make it adherent after add Australian eggplant ketenes (purchased from Shanghai Pharmaceutical Inst., Chinese Academy of Sciences), if 6 Concentraton gradient, each concentration establishes 3 multiple holes.Cell at 37 DEG C, 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 serum-free medium is washed one time, adds the MTS chromophoric solution (add 2ml solution 1 and 100 μ l solution 2 in 10ml serum-free medium, fully mix) prepared in advance according to the amount of 100 μ l/well.Do not have the hole of cell to be set to this bottom outlet by one, the bias light in order to calibration solution absorbs.Cell is put into cell culture incubator and continues cultivation 2 ~ 4 hours, then absorbance value (reference wavelength 630-700nm is read by microplate reader, measure wavelength 490nm), calculate cell survival rate, to measure the numerical value of hole absorbance value/control wells absorbance value as cell survival rate.According to cell survival rate, calculate Australian eggplant ketenes to the IC50 value of Sk-hep1 cell.
IC50 refers to the concentration of a suppressed half inhibitor.Here the concentration that SK-HEP1 cell quantity is a half Australian eggplant ketenes of contrast is.The calculating of IC50 generally needs the dosage effect of mensuration more than 5, then obtains function calculating by curve fitting and obtain.
Result: the IC50 value of Australian eggplant ketenes to Sk-hep1 cell is 61.8 μMs.
Use the same method test QGY cell (purchased from Chinese Academy of Sciences's cell bank), and the IC50 value of result Australian eggplant ketenes to QGY cell is about 89.8 μMs; Being about 59.9 μMs to the IC50 value of Focus cell, is about 910 μMs to the IC50 value of hep-G2 cell.
Embodiment 2 Australian eggplant ketenes is to the growth inhibited effect of human pancreatic cancer cell
Cck-8 test kit (Japanese colleague's chemistry institute) is utilized to detect.
Step:
1) planted in 96 orifice plates uniformly by K562 cell (purchased from Chinese Academy of Sciences's cell bank), every porocyte number is 10
4individual.
2) treat adherent, dosing after spending the night, (Australian eggplant ketenes concentration is respectively 50,16.67,5.56,1.85,0.62 μMs, and each concentration has 3 multiple holes in dosing.
3) cultivate 48 hours, complete medium is replaced to the mixture (10: 1) of serum-free medium and CCK8, hatch 2 hours in 37 DEG C of incubators.
4) be measure wavelength with 450nm, take 650nm as contrast wavelength, in microplate reader, measure reading.
Result: the IC50 value of Australian eggplant ketenes to K562 cell is 2.63 μMs.
Claims (5)
1. Australian eggplant ketenes is preparing the application in antitumor drug, and described antitumor drug is anti-leukemia medicine.
2. apply as claimed in claim 1, it is characterized in that, this antitumor drug is injection or tablet.
3. the method suppressing tumor cell in vitro to be bred, is characterized in that, is added by Australian eggplant ketenes in the culture fluid of the tumor cell of In vitro culture, and described tumor cell is hepatoma carcinoma cell or blood cell.
4. method as claimed in claim 3, it is characterized in that, described blood cell is K562 cell.
5. method as claimed in claim 3, it is characterized in that, the final concentration adding Australian eggplant ketenes is 2-100 μM.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110340486.XA CN103083331B (en) | 2011-11-01 | 2011-11-01 | Application of solanum laciniatum ketene in preparing antitumor medicines |
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| CN201110340486.XA CN103083331B (en) | 2011-11-01 | 2011-11-01 | Application of solanum laciniatum ketene in preparing antitumor medicines |
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| CN103083331A CN103083331A (en) | 2013-05-08 |
| CN103083331B true CN103083331B (en) | 2015-04-22 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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.》.2002,第37卷659-69页. * |
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